Therapeutic compositions and methods for managing treatment-related effects

Abstract

Disclosed herein are methods and compositions for preventing or reducing adverse events associated with administration of a RAS(ON) inhibitors. Thus, disclosed are compositions and methods for treating or preventing RAS(ON) inhibitor therapy-associated rash or mucositis. The methods involve administering a compound that binds to cyclophilin A (CypA) to compete with a RAS(ON) inhibitor for CypA binding, thereby reducing tri-complex formation in non-tumor tissues. These approaches may improve the tolerability of RAS(ON) inhibitor therapies without compromising efficacy.

Description

[0001] PATENT ATTORNEY DOCKET NO.: 51432-067WO2 THERAPEUTIC COMPOSITIONS AND METHODS FOR MANAGING TREATMENT-RELATED EFFECTS Background It has been well established in literature that RAS proteins (KRAS, HRAS, and NRAS) play an essential role in various human cancers and are therefore appropriate targets for anticancer therapy. Indeed, mutations in RAS proteins account for approximately 30% of all human cancers in the United States, many of which are fatal. Dysregulation of RAS proteins by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations in RAS are frequently found in human cancer. For example, activating mutations at codon 12 in RAS proteins function by inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of RAS mutant proteins to the “on” (GTP-bound) state (RAS(ON)), leading to oncogenic MAPK signaling. Notably, RAS exhibits a picomolar affinity for GTP, enabling RAS to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13C) and 61 (e.g., Q61K) of RAS are also responsible for oncogenic activity in some cancers. In normal cells, RAS proteins play a critical role in regulating cell growth, differentiation, and survival, acting as molecular switches, relaying signals from cell surface receptors to intracellular pathways that control key cellular processes. Genetic studies have demonstrated that complete deletion of RAS genes is lethal in mouse models and results in the absence of cellular proliferation in vitro (Drosten et al. Oncogene 33, 2857-2865 (2014); Drosten et al. EMBO J.29, 1091-1104 (2010)). Furthermore, KRAS conditional knockout in adult bone marrow has been shown to induce significant hematopoietic defects, including splenomegaly, an expanded neutrophil compartment, and reduced B cell number (Zhang et. al., Stem Cells; 34(7):1859-71 (2016)). There remains a need for effective and / or enhanced treatment methods for individuals suffering the effects of a RAS mutation. Summary of the Disclosure This present disclosure provides compositions containing a cyclophilin A (CypA)-binding compound for treating or preventing rash and / or mucositis, associated with treatment of a subject with a RAS(ON) inhibitor. The present disclosure therefore provides, among other things, certain pharmaceutical compositions, and methods of treating subjects suffering from or at risk of developing a rash and / or mucositis with such compositions. In an aspect, the disclosure provides a method for preventing or treating a RAS(ON) inhibitor therapy-associated skin or mucosal disorder in a subject in need thereof. The method includes topically administering prior to and / or during administration of the RAS(ON) inhibitor a topical composition comprising a CypA-binding compound to at least a portion of the skin or mucosa of the subject. In another aspect, the disclosure provides a method for reducing the risk of skin or mucosal side effects associated with RAS(ON) inhibitor therapy in a subject in need thereof. The method includes PATENT ATTORNEY DOCKET NO.: 51432-067WO2 topically administering prior to and / or during the RAS(ON) inhibitor administration a topical composition comprising a CypA-binding compound to at least a portion of the skin or mucosa of the subject. In an aspect, the disclosure provides a method for preventing or treating a RAS(ON) inhibitor induced rash in a subject in need thereof. The method includes topically administering a composition comprising a CypA-binding compound, for a period of at least 1 week (e.g., at least 2 weeks, at least 3 weeks, or at least 4 weeks) or longer to at least a portion of the skin or mucosa of the subject prior to and / or during administration of the RAS(ON) inhibitor to the subject. In a further aspect, the disclosure provides a method for preventing or treating an RAS(ON) inhibitor induced adverse effect of the skin or mucosal membranes in a subject in need thereof. The method includes administering a topical composition of a CypA-binding compound to at least a portion of the adversely affected area, wherein the adverse effect is selected from the group consisting of skin rash; skin redness; skin dryness; nail infection; cracking, swelling, or sores of the lips or corners of the mouth; dermatitis acneiform; itchy skin; stomatitis; and paronychia. In some embodiments, the adverse effect is skin rash. In some embodiments, the adverse effect is skin redness. In some embodiments, the adverse effect is skin dryness. In some embodiments, the adverse effect is nail infection. In some embodiments, the adverse effect is cracking, swelling, or sores of the lips or corners of the mouth. In some embodiments, the adverse effect is dermatitis acneiform. In some embodiments, the adverse effect is itchy skin. In some embodiments, the adverse effect is stomatitis. In some embodiments, the adverse effect is paronychia. In some embodiments of the methods described herein, the CypA-binding compound is present in the composition at a concentration of about 1% by weight to about 16% by weight. In some embodiments, the CypA-binding compound is present at a concentration of about 16% by weight or greater. In some embodiments of the methods described herein, the topical composition is administered upon initiation of or adjunct RAS(ON) inhibitor administration. In some embodiments of the methods described herein, the composition is administered at a frequency selected from the group consisting of three times daily, twice daily, and once daily. In some embodiments, the composition is administered three times daily. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered once daily. In some embodiments of the methods described herein, the topical composition is administered for a period selected from the group consisting of fourteen days, fifteen days, sixteen days, seventeen days, eighteen days, nineteen days, twenty days, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, thirteen weeks, and fourteen weeks. In some embodiments, the topical composition is administered for fourteen days. In some embodiments, the topical composition is administered for fifteen days. In some embodiments, the topical composition is administered for sixteen days. In some embodiments, the topical composition is administered for seventeen days. In some embodiments, the topical composition is administered for eighteen days. In some embodiments, the topical composition is administered for nineteen days. In some embodiments, the topical composition is administered for twenty days. In some embodiments, the topical composition is administered for three weeks. In some embodiments, the topical composition is PATENT ATTORNEY DOCKET NO.: 51432-067WO2 administered for four weeks. In some embodiments, the topical composition is administered for five weeks. In some embodiments, the topical composition is administered for six weeks. In some embodiments, the topical composition is administered for seven weeks. In some embodiments, the topical composition is administered for eight weeks. In some embodiments, the topical composition is administered for nine weeks. In some embodiments, the topical composition is administered for ten weeks. In some embodiments, the topical composition is administered for eleven weeks. In some embodiments, the topical composition is administered for twelve weeks. In some embodiments, the topical composition is administered for thirteen weeks. In some embodiments, the topical composition is administered for fourteen weeks. In some embodiments of the methods described herein, the composition is administered for a period corresponding with the RAS(ON) inhibitor administration. In some embodiments, the topical composition is administered prior to initiation of RAS(ON) inhibitor treatment. In some embodiments of the methods described herein, the composition is administered for a period selected from the group consisting of one day, two days, three days, four days five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, two weeks, three weeks, or four weeks. In some embodiments, the composition is administered for one day. In some embodiments, the composition is administered for two days. In some embodiments, the composition is administered for three days. In some embodiments, the composition is administered for four days. In some embodiments, the composition is administered for five days. In some embodiments, the composition is administered for six days. In some embodiments, the composition is administered for seven days. In some embodiments, the composition is administered for eight days. In some embodiments, the composition is administered for nine days. In some embodiments, the composition is administered for ten days. In some embodiments, the composition is administered for eleven days. In some embodiments, the composition is administered for twelve days. In some embodiments, the composition is administered for thirteen days. In some embodiments, the composition is administered for two weeks. In some embodiments, the composition is administered for three weeks. In some embodiments, the composition is administered for four weeks. In some embodiments of the methods described herein, the CypA-binding compound is selected from, or an analog or derivative thereof, cyclosporin, sanglifehrin A, NIM811 (N-methyl-4-isoleucine cyclosporin), Debio 025 (alisporivir), SCY-635, or any combination thereof. In some embodiments, the CypA-binding compound is cyclosporin. In some embodiments, the CypA binding compound is sanglifehrin A. In some embodiments, the CypA-binding compound is NIM811 (N-methyl-4-isoleucine cyclosporin). In some embodiments, the CypA-binding compound is Debio 025 (alisporivir). In some embodiments, the CypA binding compound is SCY-635. In some embodiments of the methods described herein, the topical administration of the topical composition results in reduction of a rash outbreak by about 10%, as evaluated using one of the parameters selected from a group consisting of: CTCAE v3.0 grade for rash, and / or Erythema score, and / or Lesion counts, and / or Pain VAS marked by the subject, and / or Pruritus VAS marked by the subject Photograph of face, and / or Skindex 16 and / or percentage of face surface area involvement. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In some embodiments of the methods described herein, the RAS(ON) inhibitor is selected from the group consisting of RMC-6236, RMC-6291, RMC-9805, ERAS-0015, AN9025, BPI-572270, GFH276, GFH547, compound 6A of WO 2024067857, HJ-099, RMC-7977, RCZY-680, or RCZY-690, and mixtures of any two or more thereof. In some embodiments, the RAS(ON) inhibitor is RMC-6236. In some embodiments, the RAS(ON) inhibitor is RMC-6291. In some embodiments, the RAS(ON) inhibitor is RMC-9805. In some embodiments, the RAS(ON) inhibitor is ERAS-0015. In some embodiments, the RAS(ON) inhibitor is GFH276. In some embodiments, the RAS(ON) inhibitor is GFH547. In some embodiments, the RAS(ON) inhibitor is compound 6A of WO 2024 / 067857. In some embodiments, the RAS(ON) inhibitor is HJ-099. In some embodiments, the RAS(ON) inhibitor is RMC-7977. In some embodiments, the RAS(ON) inhibitor is RCZY-680. In some embodiments, the RAS(ON) inhibitor is RCZY-690. In a further aspect, the disclosure provides a topical composition containing a CypA-binding compound, for preventing or treating a RAS(ON) inhibitor therapy induced skin or mucosal disorder in a subject in need thereof, wherein said preventing or treating comprises topically administering the composition prior to and / or during administration of the RAS(ON) inhibitor to at least a portion off the skin or mucosa of the subject. Brief Description of the Figures FIG.1A and FIG.1B show that competitive binding of CypA reduces tri-complex inhibitor potency. Detailed Description The present disclosure is based, in part, on the discovery that use of a cyclophilin A (CypA)- binding compound can reduce or prevent treatment-related toxicities associated with RAS(ON) inhibitors in normal tissues while preserving therapeutic efficacy in tissues harboring a RAS mutation. RAS(ON) inhibitors bind to chaperone protein CypA to form a binary complex, that then inhibits the RAS proteins (e.g., mutant and / or wild-type isoforms) by forming a tri-complex structure, see e.g., Schulze et al., Science, 381(6659):794-799 (2023); Holderfield et al., Nature, 629:919–926 (2024), Cregg et al., Journal of Medicinal Chemistry, 68(6):6041-6063 (2025), and Jiang et al., Cancer Discovery, 14(6):1-24 (2024). Clinical data from RAS(ON) mutant-selective inhibitors, such as elironrasib (RMC-6291), a RAS(ON) G12C-selective inhibitor (NCT05462717), and zoldonrasib (RMC-9805), a RAS(ON) G12D- selective inhibitor (NCT06040541), have shown well-tolerated safety profiles. As of April 7, 2025, the most common reported treatment-related adverse events (TRAEs) for elironrasib were QTc prolongation and GI-related toxicities that were primarily Grade 1 or 2 in severity. As of December 2, 2024, the most common TRAEs for zoldonrasib occurring in at least 10% of patients were GI-related toxicities and rash which were primarily Grade 1 or 2 in severity. Due to their ability to inhibit both mutant and wild-type RAS isoforms, RAS(ON) multi-selective inhibitors offer broad therapeutic potential. However, inhibition of wild-type RAS in non-tumor tissues (e.g., skin and mucosa) may lead to TRAEs, such as rash and mucositis, as observed in the Phase 1 clinical studies of daraxonrasib (RMC-6236) (NCT05379985), a RAS(ON) multi-selective inhibitor (data PATENT ATTORNEY DOCKET NO.: 51432-067WO2 cutoff of September 30, 2024). These TRAEs are consistent with the known on-target toxicities in normal tissues reported from other RAS pathway inhibitors. The encouraging Phase 1 data supported the initiation of Phase 3 studies of daraxonrasib in patients with PDAC (NCT06625320) or NSCLC (NCT06881784). Without being bound by theory, the inventors believe that administration of a CypA-binding compound (e.g., cyclosporin A, sanglifehrin A, and analogs or derivatives thereof) to a normal tissue can compete for binding with the RAS(ON) inhibitor to CypA in that tissue. This competitive interaction reduces formation of the RAS-inhibitory tri-complex in the treated area, thereby decreasing RAS pathway inhibition locally. In tumor tissues, for example, where no such competition occurs, the RAS(ON) inhibitor remains active and forms the tri-complex with CypA and RAS, thereby maintaining antitumor efficacy. Accordingly, the present disclosure provides methods for treating or preventing adverse events associated with RAS(ON) inhibitor therapy by administering a CypA-binding compound to tissues at risk for toxicity (e.g., topically). In certain embodiments, the methods are preventative, wherein the CypA- binding compound is administered prior to and / or concurrent with administration of a RAS(ON) inhibitor (e.g., rash or mucositis). In other embodiments, the CypA-binding compound is administered to treat or reduce existing treatment-related adverse effects. The present disclosure also provides pharmaceutical compositions comprising CypA-binding compounds formulated for local (e.g., topical or mucosal) delivery. General Methods The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of cell culturing, molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as, Molecular Cloning: A Laboratory Manual, third edition (Sambrook et al., 2001) Cold Spring Harbor Press; Oligonucleotide Synthesis (P. Herdewijn, ed., 2004); Animal Cell Culture (R. I. Freshney), ed., 1987); Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D. M. Weir & C. C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J. M. Miller & M. P. Calos, eds., 1987); Current Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction (Mullis et al., eds., 1994); Current Protocols in Immunology (J. E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Manual of Clinical Laboratory Immunology (B. Detrick, N. R. Rose, and J. D. Folds eds., 2006); Immunochemical Protocols (J. Pound, ed., 2003); Lab Manual in Biochemistry: Immunology and Biotechnology (A. Nigam and A. Ayyagari, eds.2007); Immunology Methods Manual: The Comprehensive Sourcebook of Techniques (Ivan Lefkovits, ed., 1996); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane, eds.,1988); and others. Definitions In this application, unless otherwise clear from context, (i) the term “a” means “one or more”; (ii) the term "or" is used to mean "and / or" unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only PATENT ATTORNEY DOCKET NO.: 51432-067WO2 alternatives and "and / or”; (iii) the terms “comprising” and “including” are understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) where ranges are provided, endpoints are included. As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In certain embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value). Note that when a range or amount is provided in the disclosure herein, ± 5% of each range endpoint or specific amount is included, unless otherwise indicated. For example, a range of 200 mg to 1000 mg of a RAS(ON) multi-selective inhibitor is understood to encompass 200 ± 5% mg to 1000 ± 5% mg, e.g., 190 mg to 1050 mg. As used herein, the term “administration” refers to the administration of a composition (e.g., a RAS(ON) inhibitor or a CypA-binding compound, as described herein) to a subject or system. Administration also includes administering a prodrug derivative or analog or pharmaceutically acceptable salt to the subject, which can form an equivalent amount of active compound within the subject’s body. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal or vitreal. In some embodiments, a composition comprising the RAS(ON) inhibitor compound is administered orally. In some embodiments, a composition comprising a CypA-binding compound is administered topically. Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series and any one or any and all combinations of the elements. The term "alleviating" as use herein, unless otherwise specified, refers to preventing the occurrence of rash and / or mucositis, decreasing the surface area of tissues that are affected by rash and / or mucositis, reducing the intensity of rash and / or mucositis, and / or enhancing or accelerating the rate at which these tissues heal and return to a normal or more normal state. The term “combination therapy” refers to a method of treatment including administering to a subject at least two active therapeutic agents (e.g., a RAS(ON) multi-selective inhibitor and a pan-KRAS inhibitor), optionally as one or more pharmaceutical compositions, as part of a therapeutic regimen. For example, a combination therapy may include administration of a single pharmaceutical composition including at least two therapeutic agents and one or more pharmaceutically acceptable carrier, excipient, diluent, or surfactant. A combination therapy may include administration of two or more pharmaceutical compositions, each composition including one or more therapeutic agent and one or more pharmaceutically acceptable carrier, excipient, diluent, or surfactant. The two or more agents may optionally be administered simultaneously (as a single or as separate compositions) or sequentially (as PATENT ATTORNEY DOCKET NO.: 51432-067WO2 separate compositions). The therapeutic agents may be administered in an effective amount. The therapeutic agent may be administered in a therapeutically effective amount. In some embodiments, the effective amount of one or more of the therapeutic agents may be lower when used in a combination therapy than the therapeutic amount of the same therapeutic agent when it is used as a monotherapy, e.g., due to an additive or synergistic effect of combining the two or more therapeutics. As used herein, the term “dosage form” refers to a physically discrete unit of a compound (e.g., the RAS(ON) inhibitor compound) for administration to a subject. Each unit contains a predetermined quantity of compound. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms. As used herein, the term “dosing regimen” refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic compound (e.g., a RAS(ON) multi-selective inhibitor compound) has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen includes a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen includes a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen or “therapy”). The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. The terms "inhibit," "block," and "suppress" are used interchangeably and refer to any statistically significant decrease in a biological activity, including full blocking of the activity. As used herein, the term “inhibitor” refers to a compound that prevents a biomolecule, (e.g., a protein, nucleic acid) from completing or initiating a reaction. An inhibitor can inhibit a reaction by competitive, uncompetitive, or non- competitive means, for example. With respect to its binding mechanism, an inhibitor may be an irreversible inhibitor or a reversible inhibitor. Exemplary inhibitors include, but are not limited to, nucleic acids, DNA, RNA, shRNA, siRNA, proteins, protein mimetics, peptides, peptidomimetics, antibodies, small molecules, chemicals, analogs that mimic the binding site of an enzyme, receptor, or other protein. In some embodiments, the inhibitor is a small molecule, e.g., a low molecular weight organic compound, e.g., an organic compound having a molecular weight (MW) of less than 1200 Daltons (Da). In some embodiments, the MW is less than 1100 Da. In some embodiments, the MW is less than 1000 Da. In PATENT ATTORNEY DOCKET NO.: 51432-067WO2 some embodiments, the MW is less than 900 Da. In some embodiments, the range of the MW of the small molecule is between 800 Da and 1200 Da. Small molecule inhibitors include cyclic and acyclic compounds. Small molecules inhibitors include natural products, derivatives, and analogs thereof. Small molecule inhibitors can include a covalent cross-linking group capable of forming a covalent cross-link, e.g., with an amino acid side-chain of a target protein. The term “mutation” as used herein indicates any modification of a nucleic acid or polypeptide which results in an altered nucleic acid or polypeptide. The term “mutation” may include, for example, point mutations, deletions or insertions of single or multiple residues in a polynucleotide, which includes alterations arising within a protein-encoding region of a gene as well as alterations in regions outside of a protein-encoding sequence, such as, but not limited to, regulatory or promoter sequences, as well as amplifications or chromosomal breaks or translocations. In particular embodiments, the mutation results in an amino acid substitution in the encoded protein. A “patient” or “subject” is a mammal, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, sports animals, and zoo animals including, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, and cattle. In certain embodiments, the subject has been diagnosed with cancer. In certain embodiments, the subject is a human afflicted with a tumor (e.g., cancer) who has been diagnosed with a need for treatment for a tumor (e.g., cancer). As used herein, the term “pharmaceutical composition” refers to a compound, such as a RAS(ON) inhibitor compound or a CypA-binding compound disclosed herein, or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient. A “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and noninflammatory in a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated optionally substituted hydroxyltoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxylpropyl cellulose, optionally substituted hydroxylpropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients. See, e.g., Ansel, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, PATENT ATTORNEY DOCKET NO.: 51432-067WO2 Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, a composition includes at least two different pharmaceutically acceptable excipients. The term “pharmaceutically acceptable salt,” as use herein, refers to those salts of the compounds described herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:119, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), WileyVCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid. As used herein, ‘prevent’ or ‘preventing’ refers to decreasing the incidence, lessening the severity, or avoiding the occurrence of a treatment-related adverse event in a subject.. Preventing includes prophylactic treatment. For instance, preventing can include administering to a subject a CypA- binding compound disclosed herein before the subject is administered a RAS(ON) inhibitor and the administration of the CypA-binding compound will decrease the incidence, lessen the severity, or avoid the occurrence the treatment related adverse event (e.g., rash, mucositis, or GI-related toxicity). In another embodiment, preventing can include administering to a subject a CypA-binding compound disclosed herein concurrent with administration a RAS(ON) inhibitor wherein the administration of the CypA-binding compound decreases the incidence, lessens the severity, or avoids the occurrence of treatment related adverse event. In some embodiments, preventing can include administering a CypA- binding compound to a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of a treatment related adverse event. Accordingly, the subject according to the present disclosure can be a subject at risk of developing a RAS(ON) inhibitor treatment related adverse event. The terms “RAS pathway” and “RAS / MAPK pathway” are used interchangeably herein to refer to a signal transduction cascade downstream of various cell surface growth factor receptors in which activation of RAS (and its various isoforms and allotypes) is a central event that drives a variety of cellular effector events that determine the proliferation, activation, differentiation, mobilization, and other functional properties of the cell. For example, SHP2 conveys positive signals from growth factor receptors to the RAS activation / deactivation cycle, which is modulated by guanine nucleotide exchange factors (GEFs, such as SOS1) that load GTP onto RAS to produce functionally active GTP-bound RAS as well as GTP-accelerating proteins (GAPs, such as NF1) that facilitate termination of the signals by conversion of GTP to GDP. GTP-bound RAS produced by this cycle conveys essential positive signals to a series of serine / threonine kinases including RAF and MAP kinases, from which emanate additional signals to various cellular effector functions. As used herein, the term “RAS(ON) inhibitor” refers to an inhibitor that targets, that is, selectively binds to or inhibits, the GTP-bound, active state of RAS (e.g., selective over the GDP-bound, inactive state of RAS). Inhibition of the GTP-bound, active state of RAS includes, for example, the inhibition of oncogenic signaling from the GTP-bound, active state of RAS. In some embodiments, the RAS(ON) PATENT ATTORNEY DOCKET NO.: 51432-067WO2 inhibitor is an inhibitor that selectively binds to and inhibits the GTP-bound, active state of RAS. In certain embodiments, RAS(ON) inhibitors may also bind to or inhibit the GDP-bound, inactive state of RAS (e.g., with a lower affinity or inhibition constant than for the GTP-bound, active state of RAS). In certain embodiments, a RAS(ON) inhibitor useful in the present disclosure may form a high affinity three- component complex, or conjugate, between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: the target protein of interest (e.g., RAS), and a widely expressed cytosolic chaperone (presenter protein) in the cell (e.g., cyclophilin A). More specifically, in some embodiments, the inhibitors of RAS described herein induce a new binding pocket in RAS by driving formation of a high affinity tri-complex, or conjugate, between the RAS protein and the widely expressed cytosolic chaperone, cyclophilin A (CypA). As used herein, the term “RAS(OFF) inhibitor” refers to an inhibitor that targets, that is, selectively binds to or inhibits, the GDP-bound, inactive state of RAS (e.g., selective over the GTP-bound, active state of RAS). RAS(OFF) inhibitors are known in the art and described. Non-limiting examples of RAS(OFF) inhibitors include A2A-03, ABREV01, ABT-200, ADT-030, ADT-1004, AN9025, BBP-454, BGB-53038, BI-2865, BI-2493, BI 3706674, ERAS-4, ERAS-254, ERAS-4001, HB-700 (G12X+G13D), JAB-23400, OC211, PF-07934040, QTX3034, RSC-1255, YL-17231, ZG2001, PF-07985045, ADT-007, SIL204, and HZ-V068. Non-limiting examples of RASG12C(OFF) inhibitors include adagrasib (MRTX849), divarasib (RG6330 / GDC-6036), fulzerasib (IBI351 / GFH925), garsorasib (D-1553), glecirasib (JAB-21822), olomorasib (LY3537982), opnurasib (JDQ443), sotorasib (AMG 510), ARS-853, ARS-1620, BI 1823911, BPI-421286, D3S-001, GEC255, HBI-2438, HS-10370, JAB-21000, JAB-21822, JMKX001899, JNJ-74699157 (ARS-3248), MK-1084, YL-15293, SK-17, and BI-0474. Non-limiting examples of RASG12D(OFF) inhibitors include ASP3082, BPI-501836, ERAS-4693, ERAS-5024, HBW- 012-D, HBW-012-E, HBW-012336, HRS-4642, JAB-22000, KD-8, TSN1611, LY3962673, MRTX282, MRTX1133, Q2a, SHR1127, TH-Z827, TH-Z835, TSN1611, VRTX153, DN022150, GDC-7035, AZD0022, RNK08954, INCB186748, AST2169, and QLC1101. Non-limiting examples of RASG12V(OFF) inhibitors include JAB-23000 and QTX3544. As used herein, the terms “RAS(ON) multi-selective inhibitor,” “RASMULTI inhibitor,” “RASMULTI(ON) inhibitor,” and “RAS(MULTI) inhibitor” refer to a RAS inhibitor of at least three RAS isoforms, including wild-type and / or variants with missense mutations at one of the following positions: 12, 13, 59, 61, or 146. In some embodiments, a RAS(ON) multi-selective inhibitor (e.g., daraxonrasib or RMC-6236) refers to a RAS inhibitor of at least three RAS variants with missense mutations at one of the following positions: 12, 13, and 61. Exemplary RAS(ON) multi-selective inhibitors include but are not limited to compounds described in the following patent applications, and as otherwise described herein: WO 2025119392, WO 2025087431, WO 2025051241, WO 2025045233, WO 2024249299, WO 2024222864, WO 2024206858, WO 2024169914, WO 2024153208, WO 2024149214, WO 2024104364, WO 202`4067857, WO 2024060966, WO 2024017859, WO 2024008834, WO 2023240263, WO 2023025832, WO 2022060836, WO 2021091956, CN119350371, CN 117903169, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685, and CN 117534684, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. Non- limiting examples of RAS(ON) multi-selective inhibitors also include daraxonrasib (RMC-6236), RMC- PATENT ATTORNEY DOCKET NO.: 51432-067WO2 7977, GFH547, ERAS-0015, BI-2852, BPI-572270, RCZY-690, RCZY-680 and compound 6A of WO 2024067857. As used herein, the terms “RAS(ON) mutant-selective inhibitor” refers to a RAS inhibitor selective for a RAS(ON) variant with missense mutation at one of the following positions: 12, 13, or 61. Non-limiting examples of RAS(ON) mutant-selective inhibitors include RAS(ON) G12C-selective inhibitors (e.g., elironrasib or RMC-6291), RAS(ON) G12D-selective inhibitors (e.g., zoldonrasib or RMC-9805), RAS(ON) Q61H-selective inhibitors (e.g., RMC-0708), RAS(ON) G12V-selective inhibitors (e.g. RMC-5127), and RAS(ON) G13D-selective inhibitors. RAS(ON) mutant-selective inhibitors can be found in any one of the following patent applications, and as otherwise described herein: WO 2025104149, WO 2025093625, WO 2025080946, WO 2024249299, WO 2024211663, WO 2024211712, WO 2024208934, WO 2024149819, WO 2024008610, WO 2024102421, WO 2023240263, WO 2023133543, WO 2023015559, WO 2023086341, WO 2023208005, WO 2023232776, WO 2023086341, WO 2023060253, WO 2023015559, WO 2022235870, WO 2022235864, WO 2021091967, WO 2021091982, WO 2021108683, WO 2020132597, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. A “therapeutic agent” is any substance, e.g., a compound or composition, capable of treating a disease or disorder. In some embodiments, therapeutic agents that are useful in connection with the present disclosure include RAS inhibitors and cancer chemotherapeutics. Many such therapeutic agents are known in the art and are disclosed herein. The term “therapeutically effective amount” means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence or severity of, or delays onset of, one or more symptoms of the disease, disorder, or condition. Those of ordinary skill in the art will appreciate that the term “therapeutically effective amount” does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. It is specifically understood that particular subjects may, in fact, be “refractory” to a “therapeutically effective amount.” In some embodiments, reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amount may be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated or administered in a plurality of doses, for example, as part of a dosing regimen. The term “treatment” (also “treat” or “treating”), in its broadest sense, refers to any administration of a substance (e.g., a RAS(ON) inhibitor or a CypA-binding compound of the present disclosure) that partially or completely alleviates, ameliorates, relieves, inhibits, reduces severity of, or reduces incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition (e.g., a treatment related adverse event). In some embodiments, such treatment may be administered to a PATENT ATTORNEY DOCKET NO.: 51432-067WO2 subject who exhibits early signs of the disease, disorder, or condition. Alternatively, or additionally, in some embodiments, treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, or condition. In any treatment method herein, a patient or subject may be in need of such treatment. Treatment Methods I. RAS(ON) inhibitors The present disclosure provides, inter alia, the use of a RAS(ON) inhibitor in methods of treating subjects with a RAS protein-related disease through administering the RAS(ON) inhibitor. In general, the disclosure features methods of treating a RAS protein-related disease (e.g., RAS mutant cancer) in a human subject in need thereof, the methods comprise administering an amount of a RAS(ON) inhibitor to the subject, effective to treat the RAS protein-related disease. RAS(ON) inhibitors disclosed herein may be administered or formulated in combination with an additional therapeutic agent also described herein. Moreover, the methods of the present disclosure are useful to treat or prevent RAS(ON) inhibitor treatment related adverse events. For example, the present methods can counteract or ameliorate dermal side effects, or adverse effects of administration of, a RAS(ON) inhibitor therapy. The term “side effect” is used interchangeably with the term “adverse effect.” Exemplary RAS(ON) inhibitors include RAS(ON) multi-selective inhibitors and RAS(ON) mutant-selective inhibitors. RAS(ON) multi-selective inhibitors useful in the methods according to the disclosure, can be found in any one of the following patent applications: WO 2025119392, WO 2025087431, WO 2025051241, WO 2025045233, WO 2024249299, WO 2024222864, WO 2024206858, WO 2024169914, WO 2024153208, WO 2024149214, WO 2024104364, WO 2024067857, WO 2024060966, WO 2024017859, WO 2024008834, WO 2023240263, WO 2023025832, WO 2022060836, WO 2021091956, CN119350371, CN 117903169, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685, and CN 117534684, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. The RAS(ON) multi-selective compounds useful according to the present disclosure exhibit inhibitory activities across a variety of RAS mutants. In some embodiments, a RAS(ON) multi-selective compound inhibits wild type RAS. In some embodiments, a RAS(ON) multi-selective compound inhibits wild type KRAS. In some embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at G12X, G13X, and / or Q61X, wherein X represents any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S, R, H, K, or L amino acid residue. In certain embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at G12X, wherein X represents any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S or R amino acid residue. In other embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at G13X, wherein X is any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S or R amino acid residue. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In other embodiments, a RAS(ON) multi-selective compound inhibits a RAS mutant with one or more mutations at Q61X, wherein X is any naturally occurring amino acid residue. In certain instances, X is A, C, D, V, S, R, H, K, or L amino acid residue. In other instances, X is H, K, R, or L amino acid residue. A variety of RAS proteins may be inhibited by a RAS(ON) multi-selective compound (e.g., KRAS, NRAS, HRAS, and mutants thereof at positions 12, 13 and 61, such as G12A, G12C, G12D, G12V, G12S, G12R, G13C, G13D, Q61H, Q61K, Q61R and Q61L, and others described herein, or a combination thereof). In some embodiments, a RAS(ON) multi-selective compound inhibits a G12A, G12C, G12D, G12R, G12S, G12V, or Q61H mutant of RAS, or a combination thereof. In some embodiments, the RAS(ON) multi-selective inhibitor is daraxonrasib (RMC-6236): . In some embodiments, the RAS(ON) multi-selective inhibitor is RMC-7977: .

[0002] PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In some embodiments, the RAS(ON) multi-selective inhibitor is compound 6A of WO 2024 / 067857: . In some embodiments, the RAS(ON) inhibitor is a RAS(ON) multi-selective inhibitor (e.g., daraxonrasib (RMC-6236), AN9025, BPI-572270, compound 6A of WO 2024 / 067857, ERAS-0015, GFH276, GFH547, HJ-099, RMC-7977, RCZY-680, or RCZY-690). Compositions and methods described herein may include one or more RAS(ON) inhibitors (e.g., a mutant-selective and a multi-selective inhibitor). Numerous RAS(ON) mutant-selective inhibitors have been disclosed. Some embodiments of the RAS(ON) therapies described herein include a composition comprising a RAS(ON) mutant-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12C-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12D-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G13C-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) Q61H-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12V-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G13D-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12R-selective inhibitor. RAS(ON) mutant-selective inhibitors useful according to the methods of the present disclosure, can be found in any one of the following patent applications: WO 2025104149, WO 2025093625, WO 2025080946, WO 2024249299, WO 2024211663, WO 2024211712, WO 2024208934, WO 2024149819, WO 2024008610, WO 2024102421, WO 2023240263, WO 2023133543, WO 2023015559, WO 2023086341, WO 2023208005, WO 2023232776, WO 2023060253, WO 2022235870, WO 2022235864, WO 2021091967, WO 2021091982, WO 2021108683, WO 2020132597, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. In some embodiments, the RAS(ON) mutant-selective inhibitor useful according to the present disclosure is a G12D-selective inhibitor, such as zoldonrasib (RMC-9805): PATENT ATTORNEY DOCKET NO.: 51432-067WO2 9945. In some embodiments, the RAS(ON) mutant-selective inhibitor is a G12C-selective inhibitor, such as elironrasib 4998. In some embodiments, the RAS(ON) mutant-selective inhibitor is a G12V-selective inhibitor, such as RMC-5127: . In some embodiments, the RAS(ON) mutant-selective inhibitor is a G13C-selective inhibitor, such as RMC-8839. In some embodiments, the RAS(ON) mutant-selective inhibitor is a Q61H-selective inhibitor, such as RMC-0708. In some embodiments, the RAS(ON) mutant-selective inhibitor is a G12R- selective inhibitor, such as RMC-8264. The RAS(ON) inhibitor compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes. By way of example, the RAS(ON) compounds can be synthesized using the methods described in WO 2022060836, WO 2021091956, or WO 2021091982, or any of the other RAS(ON) references cited herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. In some embodiments, the RAS(ON) inhibitor therapy may include one or more RAS(ON) inhibitors, for example, a RAS(ON) multi-selective inhibitor and a RAS(ON) mutant-selective inhibitor. In some embodiments, the RAS(ON) inhibitor therapy may include a RAS(ON) inhibitor and one or more PATENT ATTORNEY DOCKET NO.: 51432-067WO2 additional RAS inhibitors, for example, a pan-KRAS inhibitor. In some embodiments, the RAS(ON) inhibitor therapy comprises daraxonrasib and elironrasib. In some embodiments, the RAS(ON) inhibitor therapy comprises daraxonrasib and zoldonrasib. In some embodiments, the RAS(ON) inhibitor therapy comprises ERAS-0015 and ERAS-4001. In some embodiments, the RAS(ON) inhibitor therapy comprises compound 6A from WO 2024 / 067857 and a pan-KRAS inhibitor, such a pan-KRAS inhibitor in a patent application filed in the name of Medshine Discovery, Inc. II. Cyclophilin A (CypA)-binding compound Compositions and methods of the present disclosure utilize compounds that bind to cyclophilin A (CypA), a peptidyl-prolyl isomerase involved in protein folding and intracellular signaling. In certain embodiments, the CypA-binding compound functions by competitively inhibiting binding of a RAS(ON) inhibitor to CypA, thereby reducing or preventing tri-complex formation in normal tissues (i.e., tissue). This localized inhibition may attenuate on-target toxicities associated with systemic RAS(ON) inhibitor therapy, particularly in the skin and mucosa. As used herein, the term “CypA-binding compound” refers to any small molecule, peptide, or agent that directly binds to cyclophilin A with sufficient affinity to reduce or displace binding of a RAS(ON) inhibitor and is not, itself, a RAS(ON) inhibitor. Cyclophilins are a family of proteins that belong to the broader group of enzymes known as peptidyl-prolyl cis-trans isomerases (PPIases). These enzymes play a crucial role in protein folding by catalyzing the cis-trans isomerization of proline residues in peptide chains. CypA binding compounds were first elucidated with the discovery of cyclosporin A (CsA), during a screening for fungal metabolites with antibiotic properties. Isolated from the fungus Tolypocladium inflatum, CsA was initially recognized for its antifungal activity. The mechanism by which CsA exerts its immunosuppressive effects was later uncovered. It was discovered that CsA binds to CypA in T-cells. The CsA-CypA complex inhibits calcineurin, a phosphatase necessary for the activation of the nuclear factor of activated T-cells (NF-AT). This inhibition prevents the transcription of interleukin-2 (IL-2) and other cytokines critical for T-cell activation. Sanglifehrin A (SFA), a natural product, was discovered by Novartis as a novel immunosuppressant to bind to cyclophilin A but inhibits T-cell activation via a different pathway from CsA, thereby expanding the toolkit for immunosuppression. NIM811 (N-methyl-4-isoleucine cyclosporin) is a non-immunosuppressive analog of cyclosporin. It retains the ability to bind cyclophilin A but lacks immunosuppressive activity. Debio 025 (alisporivir) is another cyclosporin derivative that binds to cyclophilin A. SCY-635 binds cyclophilin A and is non-immunosuppressive, with antiviral activity against hepatitis C. Other cyclophilin A binding compounds have been subsequently discovered in the form of derivatives and analogs of those natural products, and are known in the art. CypA-binding compounds suitable for use in the compositions and methods described herein may be identified using one or more in vitro binding assays. These assays may be used to confirm binding of a candidate compound to CypA, and / or evaluate competition between the candidate compound and a RAS(ON) inhibitor for binding to CypA. The binding of a candidate CypA-binding compound to CypA can be determined using methods standard in the art, including but not limited to surface plasmon resonance (SPR), Fluorescence PATENT ATTORNEY DOCKET NO.: 51432-067WO2 Polarization (FP), isothermal titration calorimetry (ITC), or similar assay. In a non-limiting example, the binding affinity of a candidate CypA-binding compound for CypA can be assessed by SPR using, for example, a Biacore 8K instrument. CypA is immobilized on a sensor chip (e.g., a streptavidin chip), and varying candidate CypA-binding compound concentrations can be flowed over the chip in assay buffer. The SPR sensorgrams can be fitted using either a steady state affinity model or a 1:1 binding (kinetic) model to assess the CypA binding. In one embodiment, a fluorescently labeled ligand known to bind CypA is incubated with recombinant CypA protein in the presence of increasing concentrations of the test compound. Displacement of the fluorescent ligand results in a change in polarization signal, indicating binding of the test compound to CypA. In another embodiment, SPR is used to measure the direct interaction between the compound and immobilized CypA, yielding kinetic parameters and dissociation constant (KD). In one embodiment, a candidate CypA-binding compound for CypA can be determined using ITC, a label-free biophysical technique that directly measures the heat released or absorbed during molecular interactions. In a non-limiting example, purified human CypA protein is prepared in an appropriate buffer (e.g., phosphate-buffered saline or HEPES) and loaded into the sample cell of an ITC instrument (e.g., MicroCal PEAQ-ITC or equivalent). A solution of the candidate CypA-binding compound is prepared at a higher concentration and titrated stepwise into the sample cell under isothermal conditions. As the CypA- binding compound binds to CypA, the heat of binding is measured after each injection. The resulting thermogram (a plot of heat change vs. time) is integrated and fit to a binding model (e.g., one-site model) to derive binding thermodynamics, including the equilibrium dissociation constant (KD), stoichiometry (n), enthalpy (ΔH), and entropy (ΔS) of binding. The amino acid sequence of human CypA suitable for use in the binding assays described herein is known in the art and can be found, for example, at NCBI Reference Sequence NP_066953.1 and incorporated herein by reference. To identify compounds that competitively inhibit binding of a RAS(ON) inhibitor to CypA, a displacement assay may be used. In one embodiment, a fluorescently labeled or biotinylated RAS(ON) inhibitor is pre-incubated with recombinant CypA to allow binary complex formation. A test compound is then added, and the loss of signal (e.g., decreased fluorescence polarization, reduced ELISA signal, or reduced pulldown in an AlphaLISA format) is measured to assess whether the test compound displaces the RAS(ON) inhibitor from the CypA binding site. Alternatively, SPR may be used to compare binding curves of the RAS(ON) inhibitor in the presence or absence of the test compound. A shift in binding kinetics or a decrease in binding signal supports competitive interaction. In some embodiments, the activity of a CypA-binding compound may be evaluated using a cell- based viability assay that measures the CypA-binding compound’s ability to reverse or mitigate the cellular effects (e.g., cell proliferation) of a RAS(ON) inhibitor. This approach allows for assessment of CypA-binding and competition by observing restoration of RAS signaling or cellular viability. In one example, RAS mutant cancer cells (e.g., KRAS G12D or G12C mutant lines) are pre-treated with a RAS(ON) inhibitor at varying concentrations then the cells are either: re-treated with the RAS(ON) inhibitor alone, treated with the RAS(ON) inhibitor in combination with a candidate CypA-binding compound, or treated with the CypA-binding compound alone. Following the treatment period, cell PATENT ATTORNEY DOCKET NO.: 51432-067WO2 viability is measured, for example, using a luminescent viability assay (e.g., a luciferase-based ATP quantification assay such as CELLTITER-GLO® or equivalent), and luminescence is detected using a suitable plate reader. A shift in the dose–response curve or restoration of cell viability supports functional competition at the CypA binding site, consistent with reduced formation of the inhibitory RAS(ON)–CypA– RAS tri-complex. This assay format may be adapted for additional readouts such as ERK phosphorylation or gene expression profiles downstream of RAS signaling. It may also be extended to other RAS mutant cell lines or different administration schedules to characterize the kinetic and tissue-specific effects of CypA-binding compounds. Structural motifs for modulating binding between CypA and RAS(ON) inhibitors have been discussed in the art, for example, Holderfield et al., Nature, 629: 919–926 (2024) and Cregg et al., Journal of Medicinal Chemistry, 68(6):6041-6063 (2025), each of which are incorporated by reference in their entirety. In some embodiments, the CypA-binding compound useful according to the present disclosure is cyclosporin (also known as cyclosporine or ciclosporin): . In some embodiments, the CypA-binding compound is sanglifehrin A: . In some embodiments, the CypA-binding compound is NIM811: PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In some embodiments, the CypA-binding compound is alisporivir: . In some embodiments, the CypA-binding compound is SCY-635: . In some embodiments, the CypA-binding compound is Compound 3 (see, Mackman et. al., Journal of Medicinal Chemistry 61:9473-9499): . PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In some embodiments, the CypA-binding compound useful according to the present disclosure is one or more of cyclosporin A, NIM811 (N-methyl-4-isoleucine cyclosporin), alisporivir (Debio 025), SCY- 635, sanglifehrin A, Compound 3, analogs, derivatives, or pharmaceutically acceptable salts thereof. In one or more embodiments, a composition comprising a CypA-binding compound is a gel, paste, lotion, cream, soap, spray, mask, patch, powder, pomade, ointment, oil, foam, mousse, or mouth wash. In one or more embodiments, the composition is hydrophobic. In one or more embodiments, the composition comprises hydrophobic oils and waxes. In one or more embodiments, the composition comprises fatty alcohols. In one or more embodiments, the composition comprises hydrophobic oils and waxes. Accordingly, in another aspect of the present disclosure, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any such CypA-binding compound as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. It will also be appreciated that certain compounds can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. Accordingly, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as PATENT ATTORNEY DOCKET NO.: 51432-067WO2 peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Composition may be provided in any of a variety of formulations for administration to the patient by any of the various routes of pharmaceutical delivery. For instance, a composition may be administered, e.g., orally (in solid or liquid form), transdermal skin patch, etc. In certain embodiments, a composition of the present invention is administered orally in the form of a mouth rinse (mouthwash); an ingested solid, or liquid; or a lozenge, troche, or rapidly disintegrating form. In cases of mucositis in the lower gastrointestinal tract, which may be accompanied by diarrhea, the composition may take the form of an enema. In all such cases the composition contains a therapeutically effective amount of a CypA- binding compound (e.g., 1%-20% wt / wt,1%-10% wt / wt, 2%-8% wt / wt, 2.5% wt / wt, or 5% wt / wt), together with a pharmaceutically acceptable carrier or vehicle and one or more optional excipients appropriate for the desired route and manner of administration. The compositions for use in the disclosed methods can be prepared in any known or otherwise effective dosage or product form suitable for use in providing topical or local delivery of the CypA-binding compound to the affected area, which would include both pharmaceutical dosage forms as well as nutritional product forms suitable for use in the methods described herein In certain embodiments, compositions are administered as oral dosage forms or products that rapidly coat or come in contact with the oral and / or esophageal mucosa, to thus provide more effective contact with the affected mucosal tissue. Suitable formulations for topical administration to oral mucosa include liquid formulations (e.g., for mouthrinse, gargle, swish, mouthwash, spray, etc.), solid dosage forms which dissolve in the mouth, and semisolid dosage forms which are applied to coat oral surfaces. Dosage or product forms of this sort include mouthwashes which the individual may swish and swallow or swish and spit out. Suitable dosage forms also include oral lozenges, tablets, gels, and other forms described herein. Compositions and methods are useful in any pharmaceutical or nutritional liquid product form that can directly or indirectly affect those areas of skin or mucosa which have become or will likely develop an adverse event following administration of a RAS(ON) inhibitor therapy. Pharmaceutical compositions of the present invention are prepared by any known or otherwise effective method for formulating or manufacturing the selected product form. For example, the CypA- binding compound can be formulated along with common excipients, diluents, or carriers, and formed into oral tablets, capsules, sprays, mouth washes, mouth washes, swishes, lozenges, treated substrates (e.g., oral or topical swabs, pads, or disposable, non-digestible substrate treated with the compositions of the present invention); oral liquids (e.g., suspensions, solutions, emulsions), powders, or any other suitable dosage form for topical administration to oral mucosa. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In certain embodiments, the CypA-binding compound described herein are formulated as elixirs or solutions for convenient topical oral administration. Compositions of the present invention include pharmaceutical dosage forms such as lozenges, troches, or pastilles. These are typically discoid-shaped solids containing the active ingredient in a suitably flavored base. The base may be a hard sugar or sugar-free candy, glycerinated gelatin, or the combination of sugar with sufficient mucilage to give it form. Troches are placed in the mouth where they slowly dissolve, liberating the active ingredient for direct contact with the affected mucosa. Troche embodiments are prepared, for example, by adding water slowly to a mixture of the powdered active, powdered sugar, and a gum until a pliable mass is formed. A 7% acacia powder can be used to provide sufficient adhesiveness to the mass. The mass is rolled out and the troche pieces cut from the flattened mass, or the mass can be rolled into a cylinder and divided. Each cut or divided piece is shaped and allowed to dry, to thus form the troche dosage form. If the active ingredient is heat stable or can be rendered heat stable by the use of appropriate processing precautions, it may be prepared in the form of a hard candy base. For example, sugar containing syrup can be concentrated to the point where it becomes a pliable mass. The active ingredient is then added to the mass, which is then kneaded while warm to form a homogeneous mass. The homogeneous mass is gradually worked into a pipe form having the diameter desired for the candy piece. Lozenges can be cut or sectioned off from the pipe and allowed to cool. If the active ingredient is heat labile, it may be made into a lozenge preparation by compression. For example, the granulation step in the preparation is performed in a manner similar to that used for any compressed tablet. The lozenge is made using heavy compression equipment to give a tablet that is harder than usual as it is desirable for the dosage form to dissolve or disintegrate slowly in the mouth. Ingredients are preferably selected to promote slow-dissolving characteristics. In certain embodiments, the CypA-binding compound is provided in a form suitable for topically treating the oral mucosa. Such compositions are topically administered to the oral mucosa and then swallowed or spit out. Formulation types suitable for this route of administration include liquids applied as mouth rinses; solid dosage forms that may dissolve in the mouth; and semisolids that may be applied to oral cavity surfaces. Stability of the various CypA-binding compounds varies greatly with structure. However, solids for re-constitution as aqueous based solutions or suspensions prepared either by the patient or by a pharmacist prior to administration to the patient can be used, even for the less stable members of the class. In some cases, the stability of a compound in aqueous solutions is pH dependent. Procedures for choosing the optimum pH and buffering agents are well known. Other factors that affect stability in solution are also well known. For example, antioxidants may be added to reduce the rate of degradation due to oxidation. In addition to the CypA-binding compound, an aqueous liquid preparation may contain buffers, surfactants, humectants, preservatives, flavorings, stabilizers (including antioxidants), colorants, and other additives used in preparations administered into the oral cavity. In other embodiments, the CypA- binding compound may be in solution wholly or in part as a suspension to provide liquid compositions. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In certain embodiments, compositions used as mouthwashes have a pH of about 3.5 to about 8. A pH of about 4 to about 6.5 is also contemplated. One of ordinary skill in the art would appreciate that a preparation having a pH of less than about 4 would be likely to cause a stinging sensation and preparations having a higher pH are often unpleasant to use. However, one of ordinary skill in the art would recognize that such unpleasant characteristics can be masked or otherwise made less troublesome for administration. The preparations are buffered as necessary to provide the appropriate pH. Appropriate buffer systems can include citrate, acetate, tromethamine and benzoate systems. However, any buffer system commonly used for preparing medicinal compositions would be appropriate. Suitable vehicles include water, alcohols, glycols (polyethylene glycol or polypropylene glycol are examples), glycerin, and the like which are used to solubilize or suspend the active agent(s). Such formulations also optionally include surfactants, which include anionic, nonionic, amphoteric, and cationic surfactants. Such surfactants are known in the art as appropriate ingredients for mouthwashes. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Liquid formulations may contain additional components to improve the effectiveness of the product. For example, component(s) may be added to increase viscosity to provide improved retention on the surfaces of the oral cavity. Suitable viscosity increasing agents include carboxyalkyl, hydroxyalkyl, and hydroxyalkyl alkyl celluloses, xanthan gum, carrageenan, alginates, pectins, guar gum, polyvinylpyrolidone, and gellan gums. High viscosity formulations may cause nausea in chemotherapy and radiation patients and are therefore not preferred. Gellan gums are sometimes preferred as viscosity modifying agents since aqueous solutions containing certain gellan gums may be prepared so that they will experience an increase in viscosity upon contact with electrolytes. Saliva contains electrolytes that may interact with such a gellan containing solution so as to increase their viscosity. In certain embodiments, compositions of the present invention comprising a CypA-binding compound are film-forming or otherwise provide a coating effect on oral mucosa. In other embodiments, compositions of the present invention are formulated to contain a mucoadhesive polymer, a viscous polymer gel or a hydrogel, by adaptation of the materials and methods of WO 2004032843. For instance, a formulation can contain a CypA-binding compound and at least one cationic polymer or a neutral polymer that becomes cationic upon contact with an aqueous medium such as saliva, thus providing a mucoadhesive or gel forming material. The cationic polymer can be any pharmaceutically acceptable natural or synthetic polymer which has the desired physical or chemical properties to enhance retention in the mouth. Polymers will typically PATENT ATTORNEY DOCKET NO.: 51432-067WO2 be cationic polymers, mucoadhesive polymers or polymers which form a gel or hydrogel that physically adheres to the mucosa. In certain embodiments, the cationic polymer is a natural polymer such as gelatin or chitosan. Most synthetic polymers including a relatively high number of carboxylic groups will be mucoadhesive. In certain embodiments, compositions of the present invention comprise one or more natural polymers. Exemplary natural polymers include zein, modified zein, casein, gelatin, gluten, chitosan, collagen, polysaccharides such as cellulose, dextrans, polyhyaluronic acid, and alginic acid, hi other embodiments, compositions of the present invention comprise one or more synthetic polymers. Exemplary synthetic polymers include poly(vinyl) alcohols, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyvinyl esters, PVP, alkyl cellulose (ethyl cellulose, methyl cellulose, etc.), hydroxyalkyl cellulose (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, etc.), and the like. Other suitable gel or hydrogel forming polymers are well known to one of ordinary skill in the art. Other suitable polymers are biodegradable. Suitable materials and methods are as disclosed in WO 2004032843. Liquid bandages are well known to one of ordinary skill in the art. According to another embodiment, the present invention provides a composition in the form of a liquid bandage comprising a CypA-binding compound. In certain embodiments thereof, a composition comprising a CypA-binding compound and one or more of propylene glycol, polyvinylpyrrolidone (also known as povidone or PVP), or hyaluronic acid or a salt thereof, and optionally a flavoring agent and / or a local anesthetic agent. In other embodiments, compositions of the present invention optionally further comprise glycyrrhetinic acid. In certain embodiments, hyaluronic acid, or salt thereof, is present in weight percentages ranging from about 0.01% to about 5%. In other embodiments, hyaluronic acid, or salt thereof, is present in about 0.1%. According to another embodiment, glycyrrhetinic acid is present in an amount ranging from about 0.01% to 3% by weight. According to yet another embodiment, PVP is present in an amount ranging from about 1% to about 20% by weight. Flavorings used in the mouthrinse art such as peppermint, citrus flavorings, berry flavorings, vanilla, cinnamon, and sweeteners, either natural or artificial, may be used. Flavorings that are known to increase salivary electrolyte concentrations may be added to increase the magnitude of the viscosity change. The increased viscosity will promote retention of the solutions in the oral cavity and provide greater effectiveness due to increased contact time with the affected tissues. In order to improve the patient acceptability, it is desirable to add an appropriate coloring and / or flavoring material. Any pharmaceutically acceptable coloring or flavoring material may be used. Additionally, any of the mouthwash, mouthrinse, liquid bandage, and other liquid compositions of this invention may be chilled to a temperature below body temperature, in some cases below room temperature, e.g., between 30oC and 40°C, before administration to the patient. Compositions optionally further comprise one or more other active ingredients such as antibacterials, disinfectants, antifungals, analgesics, emollients, local anesthetics, and the like. Additional antimicrobial preservatives may be components of the formulation in cases where it is necessary to inhibit microbial growth. Suitable preservatives include, but are not limited to the alkyl parabens, benzoic acid, and benzyl alcohol. The quantity of preservative may be determined by PATENT ATTORNEY DOCKET NO.: 51432-067WO2 conducting standard antimicrobial preservative effectiveness tests such as that described in the United States Pharmacopoeia. Suitable solid dosage forms include powders or tablets that are designed for constitution as solutions by dissolution or suspension in a liquid vehicle and include troches, pastilles, or lozenges that dissolve slowly in the mouth. For convenience of use, solids designed to be dissolved to prepare a liquid dosage form prior to administration are rapidly dissolving. Technologies to produce rapidly dissolving solids are well known in the art. These include spray-drying, freeze-drying, particle size reduction and optimizing the pH of the dissolution medium. In another embodiment, the dosage form is a concentrated gel that is optionally diluted prior to administration. Such concentrated gels may be diluted with water prior to administration. In certain embodiments, a unit dosage form for topical or local administration to the skin or oral mucosa comprising a CypA-binding compound and optionally a pharmaceutically acceptable carrier, adjuvant, or vehicle. Such unit dosage forms for use herein comprise any of the formulations described above and herein for topical or local administration of a CypA-binding compound. Other medicinal agents may be added for the purpose of alleviating other undesirable conditions in the mouth. Such agents may include, for example, local anesthetics, anti-infective agents, and emollients. Examples of local anesthetics are lidocaine and a eutectic mixture of lidocaine and prilocaine. Lidocaine is administered in solution at a concentration of 2%, at a dose of 15 ml, at intervals of not less than three hours. The eutectic mixture is equimolar, administered at a total concentration of up to 5%. Either could be incorporated in an aerosol at similar doses. The various compositions may include additional ingredients, such as analgesics for pain relief, antibiotics to lower the risk of or to treat infection, and other agents which might help treat mucositis or promote wound healing. Liquid compositions of the invention may further include a thickening or adhesive agent such as a mucosal-adhesive water-soluble polymer or biocompatible reverse-thermal gelation polymer to help prolong the contact of mucosa with drug, alleviate pain and / or avoid infection. In some other embodiments, the composition may include an agent which promotes cell penetration by the CypA- binding compound. In one or more embodiments, the composition is given as an adjunct to treatment with a RAS(ON) inhibitor therapy. In one or more embodiments, the composition is given prophylactically before onset of a RAS(ON) inhibitor treatment related adverse event (e.g., rash, mucositis, and / or GI-related toxicity). In one or more embodiments, the composition is administered at the beginning of the RAS(ON) inhibitor therapy. In one or more embodiments, the composition is administered in parallel with RAS(ON) inhibitor therapy. In one or more embodiments, the composition is administered after the beginning of the RAS(ON) inhibitor therapy. In one or more embodiments, the composition is administered during the first week, first two weeks, first three weeks, first month, first five weeks, first six weeks, first seven weeks, first eight weeks, first nine weeks, first ten weeks, first eleven weeks or first twelve weeks of the RAS(ON) inhibitor therapy or some similar period, which could include part of a week, such as one day, two days, three days, four days, five days, or six days. In one or more embodiments, the composition is PATENT ATTORNEY DOCKET NO.: 51432-067WO2 administered one, two, three, four, five, six, seven, or eight weeks prior to the beginning of the RAS(ON) inhibitor therapy. In one or more embodiments, there is provided a method for reducing the risk of skin and / or mucosal side effects associated with RAS(ON) inhibitor therapy in a subject in need thereof or a subject at risk of the same, the method comprising topically administering prior to and / or during the RAS(ON) inhibitor administration a topical composition comprising a CypA-binding compound to at least a portion of the skin or mucosa of the subject. In some embodiments, the composition comprises a carrier and a CypA-binding compound. In some embodiments, the composition comprises a carrier, a CypA-binding compound, and an additional active agent. In some embodiments, the composition comprises a propellant and a foamable composition comprising a carrier and a CypA-binding compound. In one or more embodiments, there is provided a method for preventing or treating a RAS(ON) inhibitor therapy-induced rash and / or mucositis in a subject in need thereof or a subject at risk, the method comprising topically administering a composition comprising a CypA-binding compound, for a period of at least 2 weeks, to at least a portion of the skin or mucosa of the subject prior to and / or during administration of the RAS(ON) inhibitor to the patient, wherein the RAS(ON) inhibitor therapy comprises one or more of RMC-6236, RMC-6291, RMC-9805, AN9025, BPI-572270, GFH276, GFH547, HJ-099, RMC-7977, RCZY-680, or RCZY-690, ERAS-0015, or compound 6A of WO 2024 / 067857. In an embodiment, there is provided a method for preventing or treating an RAS(ON) inhibitor induced adverse effect of the skin or mucosal membranes in a subject in need thereof, the method comprising administering a topical formulation of a CypA-binding compound to at least a portion of the adversely affected area; wherein the adverse effect is selected from the group consisting of skin rash; skin redness; skin dryness; nail infection; cracking, swelling, or sores of the lips or corners of the mouth; dermatitis acneiform; itchy skin; stomatitis; and paronychia. Provided herein is a method for preventing, protecting, ameliorating, retarding, alleviating, arresting, or reversing the progression of a RAS(ON) inhibitor induced skin or mucosal disorder in a subject in need thereof or a subject at risk, comprising topically administering, prior to and / or during a treatment regimen including administration of the RAS(ON) inhibitor, a composition, such as a hydrophobic composition, comprising a CypA-binding compound to a target area on the skin or mucosa that is susceptible to developing the disorder. Provided herein is a method for reducing the risk of introducing changes in an oncological treatment regimen that may lower the chances of success of the regimen when administered to a subject diagnosed with cancer, the regimen involving the administration of a RAS(ON) inhibitor therapy, the method comprising administering topically, prior to and / or during RAS(ON) inhibitor administration, a composition, such as a hydrophobic composition, comprising a CypA-binding compound to a target area on skin or mucosa that is susceptible to developing a disorder induced by the RAS(ON) inhibitor. Provided herein is a method for preventing, protecting, ameliorating, retarding, alleviating, arresting, or reversing the progression of a RAS(ON) inhibitor therapy associated-rash and / or mucositis in a subject having cancer, comprising administering topically, for a period of at least 2 weeks, to a target area on skin or mucosa that is susceptible to developing or having a RAS(ON) inhibitor therapy-rash PATENT ATTORNEY DOCKET NO.: 51432-067WO2 and / or mucositis, a composition, such as a hydrophobic composition, comprising a CypA-binding compound, and wherein a part of the period is prior to the administration of the inhibitor. In one or more embodiments, the RAS(ON) inhibitor therapy associated rash is a side effect of the RAS(ON) inhibitor. In one or more embodiments, the RAS(ON) inhibitor treatment related adverse event is selected from the group consisting of a rash, a rash unrelated to the follicular unit, a papulopustular rash, pain derived from rash, pruritus, and a pruritic rash. In an embodiment, topical administration of a composition comprising a CypA-binding compound, such as a hydrophobic composition, to a subject in need thereof is once or more times daily providing effective delivery of the CypA-binding compound to the site, leading to reduction in the RAS(ON) inhibitor therapy associated rash. In an embodiment, the compositions herein are able to reduce the symptoms and severity of RAS(ON) inhibitor therapy associated rash. In an embodiment, improvement is apparent as the restoration of visible, normal cutaneous topographic features, indicating the return of skin integrity. In one or more embodiments, topical application of a composition comprising a CypA-binding compound can help avoid or ameliorate side effects of RAS(ON) inhibitor-associated rash, which, for example, may be generated upon use of RAS(ON) inhibitors with other pharmaceuticals or treatments, or may be generated upon use of RAS(ON) inhibitors alongside exposure to radiation, and may act to prevent or minimize such side effects, thereby leading to better patient compliance compared to available treatment options. In one or more embodiments, topical application of a composition comprising a CypA-binding compound is effective in reducing the adverse event by one grade or at least one grade. In some embodiments, it is effective in reducing the adverse event by two grades. In some embodiments, it is effective in reducing the adverse event by three grades. In some embodiments, it is effective in resolving the adverse event. In some embodiments, it is effective after applying daily for 1 week, or for two weeks or for three weeks or for four weeks or for five weeks or for six weeks or for seven weeks or for eight weeks. In one or more embodiments, it is applied twice daily, or thrice daily, or four times daily, or five times daily or six times daily, instead of once daily. In one or more embodiments, the topical composition for preventing, alleviating, or treating a RAS(ON) inhibitor therapy-associated rash or mucositis comprises a combination of a CypA-binding compound and a second active agent. In one or more embodiments, the second active agent is selected from the group consisting of steroids, corticosteroids, retinoids, benzoyl peroxide, salicylic acid, non- steroidal anti-inflammatory drugs, immunomodulators, imiquimod, pimecrolimus, tacrolimus, antibiotics, penicillins, antifungals, antivirals, and a mixture of any two or more thereof. In one or more embodiments, topical administration of a CypA-binding compound provided herein to a subject under RAS(ON) inhibitor therapy or prior to such therapy prevents or protects or reduces the outbreak of rash by about or at least about 10%, by about or at least about 20%, by about or at least about 30%, by about or at least about 40%, by about or at least about 50%, by about or at least about 60%, by about or at least about 70%, by about or at least about 80%, by about or at least about 90%, or by about 100%, as evaluated using a cutaneous toxicity grade, and / or Common Terminology Criteria for Adverse Events (CTCAE) v3.0 grade for rash, and / or Erythema score, and / or Lesion counts, and / or Pain PATENT ATTORNEY DOCKET NO.: 51432-067WO2 VAS marked by the subject, and / or Pruritus VAS marked by the subject Photograph of face, and / or Skindex 16 and / or percentage of face surface area involvement. In one or more embodiments, the prevention or reduction of a rash outbreak is achieved about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, or more than about 10 weeks after the start of a CypA- binding compound topical treatment. In one or more embodiments, a CypA-binding compound composition acts by protecting or partially protecting the skin or mucosa from the effects of a RAS(ON) inhibitor therapy, for example, by providing a level of protection against RAS(ON) inhibitor therapy-associated rash and / or mucositis. In one or more embodiments, the CypA-binding compound composition for use in the methods provided herein results in a decrease of at least about 40% in the number of the RAS(ON) inhibitor associated rash lesions in the area covered by the lesions, or in the severity of the lesions, when the composition is administered daily. In one or more embodiments, the decrease is at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 35%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%. In one or more embodiments, the composition for use in the methods provided herein slows or reduces or ameliorates or prevents the development of a moderate to severe RAS(ON) inhibitor- associated rash and / or reduces or ameliorates the severity of such a rash in at least about 25% of patients undergoing treatment with one or more RAS(ON) inhibitors, or at least in about 30% of the patients, or at least in about 35% of the patients, or at least in about 40% of the patients, or at least in about 45% of the patients, or at least in about 50% of the patients, or at least in about 55% of the patients, or at least in about 60% of the patients, or at least in about 65% of the patients. In one or more embodiments, the amelioration, reduction or slowing is expressed by a decrease in the number of lesions / rash, or area of lesions / rash, or intensity of lesions / rash or severity of lesions / rash or density of lesions / rash in a given area, e.g., face. In one or more embodiments prevention means, for example, the absence of appearance of a rash of significance or the absence of a significant worsening or deterioration in the rash. In one or more embodiments, prevention is expressed by the absence of a significant increase in one or more of these parameters. In one or more embodiments reduction is expressed, for example, by a reduction in one of the above parameters in an individual or in a pool of individuals by about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or more. In one or more embodiments amelioration is expressed, for example, by a change in grading, e.g., based on recognized scales, such as MESTT, or Scope Scale, of one or more of the above parameters in an individual or in a pool of individuals. Grading can include, for example, from severe to moderate, or from moderate to mild or from mild to normal or from severe to mild or from moderate to normal or any other such recognized clinical method of assessing a clinical trial and grading the patients. In one or more embodiments, grading can be based on quality-of-life scales, such as QOL, or QOLS, or DLQI (Dermatology Life Quality Index). In one of one or more embodiments, slowing is expressed by an increase in time before the appearance of a rash or development of a rash is seen in a given pool of individuals or in an individual. This increase in time may be about a day, or about two days, or about three PATENT ATTORNEY DOCKET NO.: 51432-067WO2 days, or about four days, or about five days, or about six days, or about seven days, or about eight days, or about nine days, or about ten days, or about eleven days, or about twelve days, or about thirteen days, or about fourteen days, or about three weeks, or about four weeks, or about five weeks, or about six weeks, or about seven weeks. In one or more embodiments, the composition for use in the methods provided herein prevents the worsening or deterioration of a moderate to severe RAS(ON) therapy-associated rash in at least about 25% of patients undergoing treatment with one or more RAS(ON) inhibitors, or at least in about 30% of the patients, or at least in about 35% of the patients, or at least in about 40% of the patients, or at least in about 45% of the patients, or at least in about 50% of the patients, or at least in about 55% of the patients, or at least in about 60% of the patients or at least in about 65% of the patients. In one or more embodiments, the composition for use in the methods provided herein slows or reduces or ameliorates or prevents the development of a severe RAS(ON) inhibitor therapy-associated rash (grade 3) in about 25% of the patients, or at least in about 30% of the patients, about 35% of the patients, about 40% of the patients, about 45% of the patients, about 50% of the patients, about 55% of the patients, about 60% of the patients, about 65% of the patients. In one or more embodiments, the hazard ratio of developing a more severe rash when on the placebo (vehicle) is about 0.2, which indicates a higher possibility of developing a grade 3 rash when administered with only the vehicle as compared to the compositions comprising CypA-binding compound described herein. In some embodiments, the hazard ratio of developing a more severe rash when on the placebo (vehicle) is about 0.3, or about 0.4, or about 0.5. In one or more embodiments, the odds of developing a more severe rash when on the placebo are about up to or more than 2 times higher, or about up to or more than 3 times higher, or about up to or more than 4 times higher, or about up to or more than 5 times higher, or about up to or more than 6 times higher, or about up to or more than 7 times higher, or about up to or more than 8 times higher, or about up to or more than 9 times higher, or about up to or more than 10 times higher than developing such a rash when on the composition for use in the methods provided herein. In one or more embodiments, the odds of developing a more severe rash when on the composition for use in the methods provided herein are about 2 times lower, or about 3 times lower, or about 4 times lower, or about 5 times lower, or about 6 times lower, or about 7 times lower, or about 8 times lower, or about 9 times lower, or about 10 times lower than developing such a rash when on the placebo. In one or more embodiments, the composition for use in the methods provided herein provides a lower severity score in an individual when comparing a treated area to a comparable non treated area or in a pool of individuals a lower mean and / or median severity scores compared with the placebo. In one or more embodiments, pre-emptive treatment with the compositions provided herein results in a decrease of at least one grade in rash severity in an individual. In one or more embodiments, an individual patient receiving RAS(ON) inhibitor therapy who develops a moderate to severe rash will experience a decrease in grade after five weeks or in less than five weeks, or after four weeks or in less than four weeks, or after three weeks or in less than three weeks, or after two weeks or in less than two weeks of treatment with the composition, wherein the composition is administered once, twice, or more PATENT ATTORNEY DOCKET NO.: 51432-067WO2 daily. In one or more embodiments in a pool of individuals undergoing pre-emptive treatment, there is a decrease of at least one grade in at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60% of the patients receiving RAS(ON) inhibitor therapy who develop a moderate to severe rash, after five weeks, after four weeks, after three weeks, after two weeks or in less, with the composition, wherein the composition is administered one, twice, or more daily. In some embodiments, the invention discloses a method of treating a disease or disorder that is characterized by aberrant RAS activity due to a RAS mutant. In some embodiments, the disease or disorder is a cancer. Accordingly, also provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a RAS(ON) inhibitor of the disclosure or a pharmaceutical composition comprising such a compound. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal, endometrial or melanoma. Also provided is a method of treating a RAS protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a RAS(ON) multi-selective inhibitor of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. In some embodiments, a RAS(ON) inhibitor of the disclosure, pharmaceutical compositions comprising such compounds or salts, and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. Other cancers include, for example: Cardiac, for example: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung, for example: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal, for example: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, PATENT ATTORNEY DOCKET NO.: 51432-067WO2 neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract, for example: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver, for example: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract, for example: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone, for example: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system, for example: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma); Gynecological, for example: uterus (endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic, for example: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases (e.g., myelofibrosis and myeloproliferative neoplasms, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non- Hodgkin's lymphoma (malignant lymphoma); Skin, for example: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands, for example: neuroblastoma. In some embodiments, the RAS protein is wild-type. (RASWT). Accordingly, in some embodiments, a RAS(ON) multi-selective inhibitor of the present invention is employed in a method of treating a patient having a cancer comprising a RASWT(e.g., KRASWT, HRASWTor NRASWT). In some embodiments, the RAS protein is RAS amplification (e.g., KRASamp). Accordingly, in some embodiments, a RAS(ON) inhibitor of the present invention is employed in a method of treating a patient having a cancer comprising a RASamp(KRASamp, HRASampor NRASamp). In some embodiments, the cancer comprises a RAS mutation, such as a RAS mutation described herein. In some embodiments, the cancer PATENT ATTORNEY DOCKET NO.: 51432-067WO2 comprises a KRAS G12C mutation. In some embodiments, a mutation is a G12C mutation, and one or more mutations selected from: (a) the following KRAS mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; (b) the following HRAS mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and (c) the following NRAS mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof; or a combination of any of the foregoing. In some embodiments, the cancer comprises a RAS mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In some embodiments, the cancer comprises at least two RAS mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In some embodiments, a RAS(ON) multi-selective inhibitor of the present invention inhibits more than one RAS mutant. In some embodiments, the mutation is selected from the group consisting of G12A, G12C, G12D, G12E, G12F, G12H, G12I, G12K, G12L, G12M, G12N, G12P, G12Q, G12R, G12S, G12T, G12V, G12W and G12Y, or a combination thereof, of KRAS, NRAS or HRAS. In some embodiments, the mutation is selected from the group consisting of G12H, G12I, G12K, G12M, G12N, G12P, G12Q, G12T, G12W, and G12Y, or a combination thereof, of KRAS, NRAS or HRAS. In some embodiments, the cancer is non- small cell lung cancer and the RAS mutation comprises a KRAS mutation, such as KRAS G12C. In some embodiments, the cancer is colorectal cancer and the RAS mutation comprises a KRAS mutation, such as KRAS G12C. In some embodiments, the cancer is pancreatic cancer and the RAS mutation comprises an KRAS G12C mutation. In some embodiments, the cancer is non-small cell lung. Additionally, in some embodiments, the cancer comprises a KRAS mutation selected from the group consisting of G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K and Q61L. In some embodiments, the cancer comprises an NRAS mutation selected from the group consisting of G12C, Q61H, Q61K, Q61L, Q61P and Q61R. In some embodiments, the cancer comprises a RAS mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In some embodiments, the cancer comprises at least two RAS mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In some embodiments, a RAS(ON) multi-selective inhibitor of the present invention inhibits more than one RAS mutant. For example, a compound may inhibit both KRAS G12C and KRAS G13C. A compound may inhibit both NRAS G12C and KRAS G12C. Methods of detecting RAS mutations are known in the art. Such means include, but are not limited to direct sequencing, and utilization of a high-sensitivity diagnostic assay (with CE-IVD mark), e.g., as described in Domagala, et al., Pol J Pathol 3: 145-164 (2012), incorporated herein by reference in its PATENT ATTORNEY DOCKET NO.: 51432-067WO2 entirety, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See, also, e.g., WO 2020106640. In some embodiments, the cancer is non-small cell lung cancer and the RAS mutation comprises a KRAS mutation, such as KRAS G12C, KRAS G12V or KRAS G12D. In some embodiments, the cancer is colorectal cancer and the RAS mutation comprises a KRAS mutation, such as KRAS G12C, KRAS G12V or KRAS G12D. In some embodiments, the cancer is pancreatic cancer and the RAS mutation comprises a KRAS mutation, such as KRAS G12C. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, a cancer comprises a RAS mutation and an STK11LOF, a KEAP1, an EPHA5 or an NF1 mutation, or a combination thereof. In some embodiments, the cancer is non-small cell lung cancer and comprises a KRAS G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a KRAS G12C mutation, an STK11LOFmutation, and a KEAP1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a KRAS G12C mutation and an STK11LOFmutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a KRAS G12C mutation and an STK11LOFmutation. In some embodiments, a cancer comprises a KRAS G13C RAS mutation and an STK11LOF, a KEAP1, an EPHA5 or an NF1 mutation. In some embodiments, the cancer is colorectal cancer and comprises a KRAS G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises a KRAS G12C mutation. In some embodiments, the cancer is endometrial cancer and comprises a KRAS G12C mutation. In some embodiments, the cancer is gastric cancer and comprises a KRAS G12C mutation. In some embodiments, a cancer comprises a KRAS G13C RAS mutation and an STK11LOF, a KEAP1, an EPHA5 or an NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a KRAS G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a KRAS G12V mutation. In some embodiments, the cancer is colorectal cancer and comprises a KRAS G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises a KRAS G12D mutation. In some embodiments, the cancer is pancreatic cancer and comprises a KRAS G12V mutation. In some embodiments, the cancer is endometrial cancer and comprises a KRAS G12C mutation. In some embodiments, the cancer is gastric cancer and comprises a KRAS G12C mutation. In any of the foregoing, a RAS(ON) inhibitor may inhibit RASWT(e.g., KRASWT, HRASWTor NRASWT) or RASamp(e.g., KRASamp, HRASampor NRASamp) as well. Response rates or results for subjects administered the RAS(ON) inhibitor therapy in the methods disclosed herein can be measured in various ways, after the subject has been taking the RAS(ON) inhibitor therapy a suitable length of time, as is known to those of skill in the art. In some embodiments, a RAS(ON) inhibitor of the disclosure is administered in treatment regimens. In some embodiments, the treatment regimen is 7 days. In some embodiments, the treatment regimen is 21 days. In various embodiments, the subject undergoes 1, 2, 3, or more treatment regimens. In some embodiments, the subject undergoes at least 3 treatment regimens, at least 5 treatment regimens, at least 8 treatment regimens, at least 10 treatment regimens, or at least 15 treatment regimens. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In various embodiments, the subject is administered a RAS(ON) inhibitor of the disclosure for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, e.g., for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months or longer. In various embodiments, the subject is administered a RAS(ON) inhibitor of the disclosure for at least 1 month. In various embodiments, the subject is administered a RAS(ON) inhibitor of the disclosure for at least 3 months. In various embodiments, the subject is administered a RAS(ON) inhibitor of the disclosure for at least 6 months. In various embodiments, the subject is administered a RAS(ON) inhibitor of the disclosure for at least 8 months. In some embodiments, the subject being treated by a RAS(ON inhibitor of the disclosure in the disclosed methods is one who has undergone at least one or more prior systemic cancer therapies (e.g., a RAS(ON) inhibitor of the disclosure is a second or third line therapy). In some embodiments, the subject being treated by a RAS(ON) inhibitor of the disclosure in the disclosed methods is one who has disease progression following at least one prior systemic cancer therapy (i.e., a RAS(ON) inhibitor of the disclosure is a second line therapy). In some embodiments, the subject being treated by a RAS(ON) inhibitor of the disclosure in the disclosed methods is one who has disease progression following at least two prior systemic cancer therapies (i.e., a RAS(ON) inhibitor of the disclosure is a third line therapy). Prior systemic cancer therapies can be any therapy approved by a regulatory authority (e.g., the FDA or EMA) as treatment given type and stage of cancer. In some cases, the prior systemic cancer therapy is a cancer therapy not yet approved by a regulatory' authority but undergoing clinical trials. If a subject has had a prior systemic cancer therapy, in some cases, the subject has not undergone any systemic cancer therapy for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months prior to starting therapy as disclosed herein with a RAS(ON) multi- selective inhibitor of the disclosure. The subject can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009). RECIST v1.1 is discussed in detail in the examples below. An at least stable disease is one that is a stable disease, has shown a partial response (PR) or has shown a complete response (CR) (i.e., “at least SD” = SD+PR+CR, often referred to as disease control). In various embodiments, the stable disease has neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD). In various embodiments, the patient exhibits at least a partial response (i.e., “at least PR” = PR+CR, often referred to as objective response). Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases. In various embodiments, the progression of a patient’s disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient PATENT ATTORNEY DOCKET NO.: 51432-067WO2 using a computerized tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof. Several criteria and definitions published in the literature can be used to determine the effect of one or more treatments on tumors in a subject suffering from cancer. Based on these criteria, tumors are defined as “responsive,” “stable,” or “progressive” when they improve, remain the same, or worsen during treatment, respectively. The amount of a tumor in an individual is the "tumor burden" which can be measured as the number, volume, and / or weight of the tumor. Examples of the commonly used criteria published in the literature include Response Evaluation Criteria in Solid Tumors (RECIST), Modified Response Evaluation Criteria in Solid Tumors (mRECIST), PET Response Criteria in Solid Tumors (PERCIST), Choi Criteria, Lugano Response Criteria, European Association for the Study of the Liver (EASL) Criteria, Response Evaluation Criteria in the Cancer of the Liver (RECICL), and WHO Criteria in Tumor Response. As used herein, "progression free survival" or “PFS” is the time from treatment to the date of the first confirmed disease progression per RECIST 1.1 criteria. In various embodiments, the patient exhibits a PFS of at least 1 month. In various embodiments, the patient exhibits a PFS of at least 3 months. In some embodiments, the patient exhibits a PFS of at least 6 months. “RECIST” shall mean an acronym that stands for “Response Evaluation Criteria in Solid Tumors” and is a set of published rules that define when cancer patients improve (“respond”), stay the same (“stable”) or worsen (“progression”) during treatments. Response as defined by RECIST criteria have been published, for example, a Journal of the National Cancer Institute, Vol.92, No.3, Feb.2, 2000, and RECIST criteria can include other similar published definitions and rule sets. One skilled in the art would understand definitions that go with RECIST criteria, as used herein, such as “Partial Response (PR),” “Complete Response (CR),” “Stable Disease (SD)” and “Progressive Disease (PD).” As used herein, "survival" refers to the subject remaining alive, and includes overall survival as well as progression free survival. As used herein, "reducing the tumor," means reducing the size, volume, or weight of the tumor, reducing the number of metastases, reducing the size or weight of a metastasis, or combinations thereof. In certain embodiments, a metastasis is cutaneous or subcutaneous. Thus, in certain embodiments, administration of the immune checkpoint inhibitor reduces the size or volume of the tumor by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98% or at least about 99%, for example, relative to a control drug in a subject of the same genotype. In certain embodiments, administration of the RAS(ON) multi-selective inhibitor therapy, reduces the weight of the tumor by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98% or at least about 99%, for example, relative to a control drug in a subject of the same genotype. In certain embodiments, administration of the RAS(ON) multi-selective inhibitor therapy, reduces the size or volume of a metastasis by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at PATENT ATTORNEY DOCKET NO.: 51432-067WO2 least about 98% or at least about 99%, for example, relative to a control drug in a subject of the same genotype. In certain embodiments, administration of the RAS(ON) inhibitor therapy or combination therapy comprising the same, reduces the number of metastases by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98% or at least about 99% for example, relative to a control drug in a subject of the same genotype. In certain embodiments, combinations of these effects are achieved. In some embodiments, a biological sample obtained from the subject is used to determine response to treatment with the RAS(ON) inhibitor therapy. As used herein, the term "biological sample" refers to any sample obtained from a subject. A biological sample can be obtained from a subject prior to or subsequent to a diagnosis, at one or more time points prior to or following treatment or therapy, at one or more time points during which there is no treatment or therapy or can be collected from a healthy subject. The biological sample can be a tissue sample or a fluid sample. In certain embodiments, the biological sample includes a tissue sample, a biopsy sample, a tumor aspirate, a bone marrow aspirate, or a blood sample (or a fraction thereof, such as blood or serum). In certain embodiments, the biological sample includes a tumor cell or cancer cell, for example a circulating tumor cell present in a fluid sample, for example, blood or a fraction thereof. In certain embodiments, the biological sample includes a cell free nucleic acid present in a fluid sample, for example, blood or a fraction thereof. In one embodiment, the biological sample comprises a cell lysate (or lysate fraction) or cell extract; or a solution containing one or more molecules derived from a cell or cellular material (for example a polypeptide or nucleic acid). The cell lysate can include proteins, nuclear and / or mitochondrial fractions. In certain embodiments, the cell lysate includes a cytosolic fraction. In certain embodiments, the cell lysate includes a nuclear / mitochondrial fraction and a cytosolic fraction. The source of a biological sample can be solid tissue as from a fresh, frozen and / or preserved organ, tissue sample, biopsy, or aspirate; blood or any blood constituents; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid or interstitial fluid; or cells from any time in gestation or development of the subject. The biological sample can contain compounds that are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like. The biological sample can be preserved as a frozen sample or as formaldehyde- or paraformaldehyde-fixed paraffin- embedded (FFPE) tissue preparation. For example, the sample can be embedded in a matrix, for example, an FFPE block or a frozen sample. However, other tissue and sample types are amenable for use herein. In one embodiment, the other tissue and sample types can be fresh frozen tissue, wash fluids, or cell pellets, or the like. A biological sample can be a tumor sample, which contains nucleic acid molecules from a tumor or cancer. A biological sample that is a tumor sample can be DNA, for example, genomic DNA, or cDNA derived from RNA. In one embodiment, the tumor nucleic acid sample is purified or isolated (for example, it is removed from its natural state). In one embodiment, the sample is a tissue (for example, a tumor biopsy), a CTC or cell free nucleic acid. In certain embodiments, a tumor sample is isolated from a human subject. In certain embodiments, the analysis is performed on a tumor biopsy embedded in paraffin wax. In one embodiment, the sample can be a fresh frozen tissue sample. In certain embodiments, the sample is a PATENT ATTORNEY DOCKET NO.: 51432-067WO2 bodily fluid obtained from the subject. The bodily fluid can be blood or fractions thereof (specifically, serum, plasma, urine, saliva, sputum, or cerebrospinal fluid (CSF). The sample can contain cellular as well as extracellular sources of nucleic acid. The extracellular sources can be cell-free nucleic acids and / or exosomes. The methods described herein, including the RT-PCR methods, are sensitive, precise and have multi-analyte capability for use with paraffin embedded samples. See, for example, Cronin et al., Am. J Pathol.164(1):35-42 (2004). Additional means for assessing response are described in detail in the examples below and can generally be applied to the methods disclosed herein. A subject undergoing a therapy is monitored for adverse events (AE) during the course of the therapy. A treatment related AE is an AE that is related to the treatment drug. A treatment emergent AE is one that a subject develops undergoing the treatment that was not present prior to start of therapy. In some cases, the treatment emergent AE is not or suspected not to be related to the treatment itself. AEs are characterized as one of five grades - grade l is a mild AE; grade 2 is a moderate AE; grade 3 is a severe AE; grade 4 is a life-threatening or disabling AE; and grade 5 is death related to AE. In some cases, the subject does not exhibit any grade 3 AE that is treatment related. In some cases, the subject does not exhibit any grade 3 AE. In some cases, the subject does not exhibit any grade 4 AE that is treatment related. In some cases, the subject does not exhibit any grade 4 AE. In various cases, the subject does not exhibit a grade 3 or grade 4 AE that is treatment related after administration of the RAS(ON) inhibitor therapy for at least one month, or at least three months. In various cases, the subject being treated with the RAS(ON) inhibitor therapy in the methods disclosed herein, does not exhibit any dose limiting toxicities (DLT) at the dose administered. A DLT is any AE meeting the criteria listed below occurring during the first treatment cycle of the RAS(ON) inhibitor therapy (day 1 through day 21) where relationship to the drug cannot be ruled out. In various embodiments, the disclosure provides a method of treating a RAS protein-related disease or disorder (e.g., cancer) in a subject in need thereof comprising administering to the subject the RAS(ON) inhibitor described herein. Accordingly, one embodiment of the present disclosure provides a method treating a subject in need thereof by administering a pharmaceutical composition containing the RAS(ON) inhibitor described herein, and a pharmaceutically acceptable excipient, as well as methods of using the RAS(ON) inhibitor therapy to prepare such compositions. In some embodiments, a RAS(ON) inhibitor of the disclosure is present in a pharmaceutical composition in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or nonaqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, PATENT ATTORNEY DOCKET NO.: 51432-067WO2 lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces. For use as treatment of subjects, a RAS(ON) inhibitor of the disclosure can be formulated as pharmaceutical compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, a RAS(ON) inhibitor of the disclosure is formulated in ways consonant with these parameters. A summary of such techniques may be found in Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference. Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from 0.1% to 99%, from 5% to 90%, or from 1% to 20% of a RAS(ON) inhibitor of the disclosure, by weight or volume. In some embodiments, a RAS(ON) inhibitor of the disclosure may be present in amounts totaling 1-95% by weight of the total weight of a composition, such as a pharmaceutical composition. Formulations may be prepared in a manner suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. A formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like. Compounds, or a pharmaceutically acceptable salt thereof, can be administered also in liposomal compositions or as microemulsions. For injection, formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol and the like. Such compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, and so forth. Various sustained release systems for drugs have also been devised. See, for example, U.S. Patent No.5,624,677. Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration. Oral administration is also suitable for compounds of the invention, or a pharmaceutically acceptable salt thereof. Suitable forms include syrups, capsules, and tablets, as is understood in the art. In one embodiment the therapeutically effective amount of a RAS(ON) inhibitor of the disclosure is administered orally in the form of a tablet or multiple tablets. A RAS(ON) inhibitor of the disclosure, may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Other modalities of combination therapy are described herein. The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the PATENT ATTORNEY DOCKET NO.: 51432-067WO2 administration of the unit dose to subjects, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions. The kit may be manufactured as a single use unit dose for one subject, multiple uses for a particular subject (at a constant dose or in which the individual compounds, or a pharmaceutically acceptable salt thereof, may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple subjects (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like. Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, optionally substituted hydroxylpropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like. Two or more compounds may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned. In one example, the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that a substantial portion of the second compound is released prior to the release of the first compound. Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein a RAS(ON) inhibitor of the disclosure is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein a RAS(ON) inhibitor of the disclosure is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment. Dissolution or diffusion-controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating a RAS(ON) inhibitor of the disclosure into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-optionally substituted hydroxylmethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, PATENT ATTORNEY DOCKET NO.: 51432-067WO2 carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbon. The liquid forms in which a RAS(ON) inhibitor of the disclosure, or a composition thereof, can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. In some embodiments, the pharmaceutical composition may further comprise an additional compound having antiproliferative activity. Depending on the mode of administration, compounds, or a pharmaceutically acceptable salt thereof, will be formulated into suitable compositions to permit facile delivery. Each compound, or a pharmaceutically acceptable salt thereof, of a combination therapy may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together for the simultaneous or near simultaneous administration of the agents. It will be appreciated that a RAS(ON) inhibitor of the disclosure and pharmaceutical compositions thereof can be formulated and employed in combination therapies, that is, a RAS(ON) inhibitor of the disclosure and pharmaceutical compositions thereof can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects). Administration of each drug in a combination therapy, as described herein, can, independently, be one to four times daily for one day to one year, and may even be for the life of the subject. Chronic, long-term administration may be indicated. In one aspect, the present disclosure provides methods for treating a RAS protein-related disorder in a subject where the RAS-related disorder pathology is mediated, in part, through increased signaling in the RAS / MAPK pathway. In various embodiments, the method generally comprises administering to the subject a therapeutically effective amount of a RAS(ON) inhibitor of the disclosure. In some embodiments, the RAS protein-related disorder is a RASopathy. A RASopathy is a group of genetic disorders that are caused by mutations in genes involved in the RAS / MAPK signaling pathway. RASopathies are characterized by a range of clinical features and can affect multiple organ systems, including the cardiovascular, musculoskeletal, neurological, and dermatological systems. In one aspect, the present disclosure is directed to methods of treating a disease or disorder that is characterized by aberrant RAS activity (e.g., cancer or a RASopathy). In some embodiments the disease or disorder is cancer (e.g., a cancer having one or more RAS mutations that cause aberrant RAS activity). Non-limiting examples of non-cancerous RAS related diseases or disorders are shown in Table 1. In each embodiment, the method generally comprises administering to the subject a therapeutically effective amount of a RAS(ON) multi-selective inhibitor of the disclosure. In some embodiments, the methods comprise administering RAS(ON) multi-selective inhibitor of the disclosure in combination with PATENT ATTORNEY DOCKET NO.: 51432-067WO2 one or more therapeutic agents. Suitable RAS(ON) multi-selective inhibitor of the disclosure and additional therapeutic agents are described herein. Exemplary RAS related non-cancerous indications are summarized in Table 1. Table 1: Exemplary RAS related Non-cancerous Indications In some embodiments, the methods include treating a RASopathy selected from Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Legius syndrome. While each RASopathy has unique features, they all share certain similarities, such as facial dysmorphisms, cardiac abnormalities, developmental delays, and an increased risk of certain cancers. RASopathies are typically diagnosed through a combination of clinical evaluation, genetic testing, and imaging studies. Treatment and management of RASopathies depend on the specific type and PATENT ATTORNEY DOCKET NO.: 51432-067WO2 severity of the disorder, but may include medication, surgery, and supportive therapies such as physical and occupational therapy. III. Combination Therapies The methods of the disclosure may include a RAS(ON) inhibitor of the disclosure in combination an additional therapeutic agent (e.g., a second RAS inhibitor such as a pan-KRAS inhibitor). A CypA- binding compound can be administered to the subject in need thereof prior to or during the combination therapy comprising a RAS(ON) inhibitor. The dosages of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In certain embodiments, compositions of the disclosure comprise a RAS(ON) inhibitor of the present disclosure and one additional therapeutic agent. In certain embodiments, compositions of the disclosure comprise a RAS(ON) inhibitor of the present invention and two additional therapeutic agents. In certain embodiments, compositions of the disclosure comprise a RAS(ON) inhibitor of the present invention and three additional therapeutic agents. In certain embodiments, compositions of the disclosure comprise a RAS(ON) inhibitor of the present invention and four or more additional therapeutic agents. Also provided are pharmaceutical compositions including the combinations, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Compositions comprising a combination of therapeutic agents may be used in methods of modulating RAS (e.g., in a subject or in a cell) and in methods of treating RAS related diseases and disorders (e.g., cancer), as described herein. The present disclosure provides, inter alia, compositions, methods, and kits for treating or preventing a RAS related disease or disorder. Exemplary agents that may be used in combination with a RAS(ON) inhibitor of the present disclosure are described below. All references herein are incorporated by reference for the agents described, including compound or molecular structures disclosed therein, whether explicitly stated as such or not. a) RAS / MAPK Inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more RAS / MAPK pathway inhibitors. The RAS / MAPK pathway is a signal transduction cascade downstream of various cell surface growth factor receptors in which activation of RAS (and its various isoforms and allotypes) is a central event that drives a variety of cellular effector events that determine the proliferation, activation, differentiation, mobilization, and other functional properties of the cell. SHP2 conveys positive signals from growth factor receptors to the RAS activation / deactivation cycle, which is modulated by guanine nucleotide exchange factors (GEFs, such as SOS1) that load GTP onto RAS to produce functionally active GTP-bound RAS as well as GTP- accelerating proteins (GAPs, such as NF1) that facilitate termination of the signals by conversion of GTP to GDP. GTP-bound RAS produced by this cycle conveys essential positive signals to a series of PATENT ATTORNEY DOCKET NO.: 51432-067WO2 serine / threonine kinases including RAF and MAP kinases, from which emanate additional signals to various cellular effector functions. In some embodiments, a therapeutic agent that may be combined with a RAS(ON) inhibitor is an inhibitor of the MAP kinase (MAPK) pathway (or “MAPK pathway inhibitor”). MAPK pathway inhibitors include, but are not limited to, one or more MAPK pathway inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758–1784. For example, the MAPK inhibitor may be selected from one or more of trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY- 424704 / ARRY-704); RO5126766 (Roche, described in PLoS One.2014 Nov 25;9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res.2011 Mar 1;17(5):989-1000). The MAPK pathway inhibitor may be PLX8394, LXH254, GDC-5573, or LY3009120. A MAPK pathway inhibitor may be a PI3Kα:RAS breaker, such as BBO-10203. i) RAS(OFF) inhibitors, RAS(OFF) degraders and other RAS inhibitor types Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more RAS(OFF) inhibitors. Numerous mutant-selective and pan- KRAS inhibitors have been disclosed and are known in the art. A RAS(OFF) inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor described herein. RAS(OFF) inhibitors are designed to inhibit RAS activity by targeting different regions of the RAS protein in its inactive state (GDP bound state), preventing its activation and downstream signaling. In some embodiments, a RAS(OFF) inhibitor is a KRAS(OFF) inhibitor that has a molecular weight of under 700 Da. In some embodiments, the KRAS(OFF) inhibitor is specific for a KRASG12Cmutation. KRASG12C(OFF) inhibitors use a covalent binding group that allows them to selectively target the KRASG12Cmutant protein, and many such inhibitors comprise a pyrimidine core. KRASG12C(OFF) inhibitors all target the same cysteine residue in the KRASG12Cmutant protein, leading to a conformational change that locks the protein in an inactive state. KRASG12C(OFF) inhibitors include, but are not limited to, adagrasib (MRTX849), divarasib (RG6330 / GDC-6036), fulzerasib (IBI351 / GFH925), garsorasib (D-1553), glecirasib (JAB-21822), olomorasib (LY3537982), opnurasib (JDQ443), sotorasib (AMG 510), ARS-853, ARS-1620, BI-0474, BI 1823911, BPI-421286, D3S-001, ERAS-3490, GEC255, GH35, HBI-2438, HS- 10370, JAB-21000, JAB-21822, JMKX001899, JNJ-74699157 (ARS-3248), MK-1084, SK-17, and YL- 15293. In some embodiments, the KRAS(OFF) inhibitor is selected from AMG510 and MRTX849. In some embodiments, the KRAS(OFF) inhibitor is AMG510. In some embodiments, the KRAS(OFF) inhibitor is MRTX849. In some embodiments, the KRAS(OFF) inhibitor is GDC-6036. A RAS(OFF) inhibitor may be an antibody-drug conjugate. See also doi.org / 10.1021 / acs.jmedchem.4c02929. In some embodiments, a KRAS(OFF) inhibitor is specific for a KRASG12Dmutation. Non-limiting examples of KRASG12D(OFF) inhibitors include ASP3082, AST2169, BPI-501836, DN022150, ERAS- 4693, ERAS-5024, GDC-7035 (RG6620), HBW-012-D, HBW-012-E, HBW-012336, HRS-4642, HS- 10529, INCB186748, JAB-22000, KD-8, KRB-456, LY3962673, MRTX282, MRTX1133, Q2a, QLC1101, RNK08954, SHR1127, TH-Z827, TH-Z835, TSN1611, and VRTX153. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In some embodiments, the small molecule RAS(OFF) inhibitor is specific for a KRASG12Vmutation (e.g., JAB-23000, QTX3544). In some embodiments, the small molecule RAS(OFF) inhibitor is specific for a KRASG13Dmutation. In some embodiments, a pan-KRAS inhibitor is selected from one disclosed in any of the following: WO 2025106905, WO 2025106901, WO 2025101776, WO 2025096738, WO 2025092798, WO 2025085748, WO 2025077770, WO 2025077663, WO 2025076523, WO 2025064848, WO 2025059366, WO 2025059040, WO 2025049641, WO 2025049619, WO 2025049402, WO 2025045141, WO 2025038936, WO 2025026903, WO 2025016899, WO 2025007000, WO 2025006967, WO 2025006962, WO 2025006720, WO 2025006704, WO 2024255795, WO 2024254404, WO 2024246099, WO 2024238633, WO 2024238343, WO 2024236452, WO 2024235286, WO 2024235225, WO 2024230734, WO 2024220645, WO 2024220532, WO 2024218686, WO 2024215754, WO 2024213979, WO 2024213122, WO 2024209339, WO 2024206766, WO 2024206747, WO 2024192424, WO 2024178313, WO 2024178304, WO 2024173842, WO 2024153180, WO 2024119277, WO 2024120433, WO 2024115890, WO 2024112654, WO 2024104453, WO 2024104425, WO 2024107686, WO 2024104453, WO 2024103010, WO 2024085661, WO 2024083246, WO 2024083168, WO 2024067575, WO 2024064335, WO 2024063578, WO 2024063576, WO 2024051852, WO 2024051763, WO 2024046370, WO 2024044667, WO 2024041621, WO 2024041606, WO 2024041589, WO 2024040131, WO 2024040109, WO 2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO 2024015262, WO 2024009191, WO 2024008068, WO 2024002373, WO 2023287896, WO 2023274324, WO 2023246914 (e.g., compound 14), WO 2023246777, WO 2023230190, WO 2023215802, WO 2023215801, WO 2023197984, WO 2023190748, WO 2023183585, WO 2023179703, WO 2023173017, WO 2023173016, WO 2023173014, WO 2023172737, WO 2023154766, WO 2023143352, WO 2023143312, WO 2023138589, WO 2023133183, WO 2023122662, WO 2023114733, WO 2023099624, WO 2023099623, WO 2023099612, WO 2023099608, WO 2023099592, WO 2023097227, WO 2023064857, WO 2023056421, WO 2023049697, WO 2023046135, WO 2023039240, WO 2023034290, WO 2023020523, WO 2023020521, WO 2023020519, WO 2023020518, WO 2023001123, WO 2022271823, WO 2022261210, WO 2022258974, WO 2022256459, WO 2022250170, WO 2022248885, WO 2022228543, WO 2022216762, WO 2022072783, WO 2016161361, KR 20240101190, KR 20240101189, KR 20240041720, KR 20240041719, CN 119751476, CN 119661539, CN 119371353, CN 119019382, CN 118791505, CN 118221700, CN 118126064, CN 117924327, CN 117946135, CN 117800990, CN 117800989, CN 117683051, CN 117486901, CN 117263959, CN 116969977, or CN 116332948, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. In some embodiments, combination comprising a pan-KRAS inhibitor therapy comprises ERAS-4001. In some embodiments, the pan-KRAS inhibitor is a pan-KRAS inhibitor in a patent application filed in the name of Medshine Discovery, Inc. In some embodiments, a combination comprising a pan-KRAS inhibitor therapy includes A2A-03, ABREV01, ADT-007, ABT-200, ADT-030, ADT-1004, BBP-454, BGB-53038, BI-2865, BI-2493, BI 3706674, BRSD-143, ERAS-4, ERAS-254, ERAS-4001, HB-700 (G12X+G13D), HZ- V068, ID12241161, JAB-23400, LY4066434, OC211, PF-07985045, PF-07934040, QTX2024, QTX3034, RSC-1255, SIL204, SYNB021225, YL-17231, ZG2001. In some embodiments, the pan-KRAS is selected PATENT ATTORNEY DOCKET NO.: 51432-067WO2 from one disclosed in WO 2023246914. In one embodiment, the methods of the present disclosure include administering the combination of the RAS(ON) multi-selective inhibitor, ERAS-0015, and the pan- KRAS inhibitor, ERAS-4001 using the methods described herein. In some embodiments, reference to the term RAS(OFF) inhibitor includes any such RAS(OFF) inhibitor disclosed in any one of the following patent applications: WO 2025111586, WO 2025111582, WO 2025108443, WO 2025106905, WO 2025106901, WO 2025101776, WO 2025096984, WO 2025096957, WO 2025096738, WO 2025092986, WO 2025092798, WO 2025085748, WO 2025085580, WO 2025080653, WO 2025077770, WO 2025077663, WO 2025076523, WO 2025072649, WO 2025072457, WO 2025072451, WO 2025067459, WO 2025067453, WO 2025064848, WO 2025064542, WO 2025061125, WO 2025059366, WO 2025059040, WO 2025054530, WO 2025054347, WO 2025054270, WO 2025053850, WO 2025051242, WO 2025045141, WO 2025049641, WO 2025049619, WO 2025049402, WO 2025049274, WO 2025040767, WO 2025038936, WO 2025036475, WO 2025036470, WO 2025034883, WO 2025034849, WO 2025026903, WO 2025019688, WO 2025018418, WO 2025016899, WO 2025016432, WO 2025011443, WO 2025010415, WO 2025007000, WO 2025006967, WO 2025006962, WO 2025006720, WO 2025006704, WO 2025002430, WO 2025002302, WO 2024259169, WO 2024254404, WO 2024254334, WO 2024255795, WO 2024246099, WO 2024243025, WO 2024238633, WO 2024238343, WO 2024236452, WO 2024235286, WO 2024235225, WO 2024233776, WO 2024230734, WO 2024230707, WO 2024229447, WO 2024229444, WO 2024229442, WO 2024229317, WO 2024227091, WO 2024220645, WO 2024220532, WO 2024218686, WO 2024215862, WO 2024215754, WO 2024213979, WO 2024213122, WO 2024208305, WO 2024209339, WO 2024206766, WO 2024206747, WO 2024197503, WO 2024193698, WO 2024192424, WO 2024179546, WO 2024178313, WO 2024178304, WO 2024173842, WO 2024167922, WO 2024160225, WO 2024159471, WO 2024159470, WO 2024158778, WO 2024158242, WO 2024153119, WO 2024153116, WO 2024138486, WO 2024138206, WO 2024138052, WO 2024131829, WO 2024125642, WO 2024125600, WO 2024123913, WO 2024123102, WO 2024120433, WO 2024120419, WO 2024119277, WO 2024118926, WO 2024109233, WO 2024112654, WO 2024104453, WO 2024104425, WO 2024107686, WO 2024104453, WO 2024103010, WO 2024097559, WO 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2022192790, WO 2022188729, WO 2022187411, WO 2022184178, WO 2022173870, WO 2022173678, WO 2022135346, WO 2022133731, WO 2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO 2022109485, WO 2022109487, WO 2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO 2021257828, WO 2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO 2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO 2021231526, PATENT ATTORNEY DOCKET NO.: 51432-067WO2 WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO 2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO 2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO 2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2021113595, WO 2021107160, WO 2021106231, WO 2021088458, WO 2021086833, WO 2021085653, WO 2021081212, WO 2021058018, WO 2021057832, WO 2021055728, WO 2021031952, WO 2021027911, WO 2021023247, WO 2020259513, WO 2020259432, WO 2020234103, WO 2020233592, WO 2020216190, WO 2020178282, WO 2020146613, WO 2020118066, WO 2020113071, WO 2020106647, WO 2020102730, WO 2020101736, WO 2020097537, WO 2020086739, WO 2020081282, WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 2018218071, WO 2018218069, WO 2018217651, WO 2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO 2018068017, WO 2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659, WO 2013155223, KR 20240159370, KR 20240101190, KR 20240101189, KR 20240041720, KR 20240041719, CN 119930639, CN 119909188, CN 119751476, CN 119733053, CN 119684316, CN 119684315, CN 119684314, CN 119661556, CN 119661555, CN 119661539, CN 119606974, CN 119528902, CN 119528810, CN 119504612, CN 119490514, CN 119490512, CN 119462648, CN 119371353, CN 119350242, CN 119264124, CN 119241566, CN 119060049, CN 119060066, CN 119019382, CN 118994158, CN 118994031, CN 118806919, CN 118791505, CN 118772176, CN 118754899, CN 118745175, CN 118666870, CN118666869, CN 118580238, CN 118307563, CN 118221700, CN 118221699, CN 118221698, CN 118221685, CN 118126064, CN 118078802, CN 118078801, CN 118005656, CN 117986263, CN 117986263, CN 117946135, CN 117924327, CN 117903117, CN 117800990, CN 117800989, CN 117800976, CN 117736226, CN 117683051, CN 117645627, CN 117624194, CN 117624190, CN 117586280, CN 117486901, CN 117466917, CN 117462688, CN 117362315, CN 117327102, CN 117327094, CN 117327074, CN 117285590, CN 117263959, CN 117247382, CN 117186095, CN 117164605, CN 116969977, CN 116925075, CN 116891489, CN 116731045, CN 116731044, CN 116554208, CN 116514846, CN 116478184, CN 116478141, CN 116410145, CN 116375742, CN 116354988, CN 116332948, CN 116332938, CN 116327956, CN 116262759, CN 116217592, CN 116199703, CN 116162099, CN 116143806, CN 116143805, CN 116120315, CN 116102559, CN 115960105, CN 115894520, CN 115872979, CN 115850267, CN 115785199, CN 115785124, CN 115724842, CN 115724842, CN 115721720, CN 115716840, CN 115703775, CN 115611923, CN 115611898, CN 115583937, CN PATENT ATTORNEY DOCKET NO.: 51432-067WO2 115572278, CN 115557949, CN 115521312, CN 115504976, CN 115490709, CN 115466272, CN 115433183, CN 115433179, CN 115403575, CN 115385938, CN 115385937, CN 115385912, CN 115381786, CN 115368383, CN 115368382, CN 115368381, CN 115353506, CN 115322158, CN 115304623, CN 115304602, CN 115197245, CN 115181106, CN 114989195, CN 114989166, CN 114989147, CN 114920741, CN 114920739, CN 114907387, CN 114874234, CN 114874201, CN 114716436, CN 114716435, CN 114685532, CN 114685460, CN 114591319, CN 114539293, CN 114539286, CN 114539246, CN 114437107, CN 114437084, CN 114409653, CN 114380827, CN 114195804, CN 114195788, CN 114437107, CN 114409653, CN 114380827, CN 114195804, CN 114057776, CN 114057744, CN 114057743, CN 113999226, CN 113980032, CN 113980014, CN 113960193, CN 113929676, CN 113754653, CN 113683616, CN 113563323, CN 113527299, CN 113527294, CN 113527293, CN 113493440, CN 113429405, CN 113321654, CN 113248521, CN 113087700, CN 113024544, CN 113004269, CN 112920183, CN 112778284, CN 112390818, CN 112390788, CN 112300196, CN 112300194, CN 112300173, CN 112225734, CN 112142735, CN 112110918, CN 112094269, CN 112047937, CN 109574871, US 2025115603, US 2025114346, US 2025114339, US 20240358702, US 2024270736, or EP 4389751, each of which is incorporated herein by reference in its entirety, including the RAS compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, a RAS inhibitor binds to the OFF form as well as the ON form. Non- limiting examples of such inhibitors include, e.g., pan-KRAS: ALTA3263, AMG 410, BBO-11818, HBW- 016-K, HEC211909, JAB-23E73, JAB-23425, JAB-23E73; G12C: BBO-8520, FMC-376; G12D: AZD0022, GFH375 (VS-7375), INCB161734, QTX3046, TSN1611 and TH-Z835. In some embodiments, a RAS inhibitor binds to the ON form of RAS but is not a tri-complex inhibitor, such as pan-KRAS inhibitors JTX-102 and JTX-105. In any embodiment employing a RAS(OFF) inhibitor herein, a RAS(OFF) degrader targeting the OFF state of RAS may be employed. These degraders are known in the art. RAS degraders may be found, for example, in one or more of the following applications: WO 2025108479, WO 2025107579, WO 2025103476, WO 2025096855, WO 2025085815, WO 2025083472, WO 2025078984, WO 2025076044, WO 2025058008, WO 2025053850, WO 2025024732, WO 2025019823, WO 2025006783, WO 2025006753, WO 2024263586, WO 2024261257, WO 2024261256, WO 2024241248, WO 2024233838, WO 2024199266, WO 2024188281, WO 2024 / 59164, WO 2024152247, WO 2024149214, WO 2024131777, WO 2024120424, WO 2024119278, WO 2024118966, WO 2024118960, WO 2024083258, WO 2024083256, WO 2024055112, WO 2024054625, WO 2024050742, WO 2024044334, WO 2024040080, WO 2024034657, WO 2024034593, WO 2024034591, WO 2024034123, WO 2024029613, WO 2024020159, WO 2024019103, WO 2024017392, WO 2023215906, WO 2023185864, WO 2023171781, WO 2023141570, WO 2023138524, WO 2023130012, WO 2023116934, WO 2023099620, WO 2023081476, WO 2023077441, WO 2022260482, CN 119219669, CN 119161349, CN 118955610, CN 118772249, CN 118725012, CN 118496502, CN 118496300, CN 118126040, or CN 115785199, each of which is incorporated herein by reference in its entirety. Non-limiting examples of RAS degraders include: ASP3082 (KRAS G12D); ASP4396 (KRAS G12D); BPI-585725 (G12X and WT), LT-010366 (G12D); PT0253 (G12D), RD0255359 (KRAS G12C / D / V); RP03707 (G12D). PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In some embodiments, the RAS(OFF) inhibitor is a peptide-based inhibitor. Peptide-based RAS(OFF) inhibitors have been developed that target specific regions of the RAS protein, such as the Switch II region or the RAS-effector interface. Non-limiting examples include the K-Ras-binding peptide (Krpep-2d), the Ras inhibitory peptide (RasIn) and LUNA18 (NCT05012618). Peptide-based RAS(OFF) inhibitors are a class of compounds that target the RAS protein by disrupting its interaction with its downstream effectors or other signaling proteins. These inhibitors are typically designed to mimic the binding motifs of RAS-interacting proteins or other RAS effectors, such as RAF or PI3K. By binding to RAS at the same site as these effectors, peptide-based inhibitors can effectively compete with these proteins and prevent the activation of downstream signaling pathways. See, e.g., WO 2025018418, WO 2024219480, WO 2024219446, WO 2024176153, WO 2024101402, WO 2024101386, WO 2023214576, WO 2023140329, WO 2022234853, WO 2022234852, WO 2022234851, WO 2022234639 and CN 120040551, each of which is incorporated herein by reference in its entirety. Peptide-based RAS(OFF) inhibitors can be further classified into two main categories: those that target the RAS-effector interface, and those that target other regions of the RAS protein. Peptide-based inhibitors that target the RAS-effector interface are designed to bind to the switch regions of RAS that are critical for its interaction with downstream effectors, such as RAF or PI3K. These inhibitors typically contain amino acid residues that are similar to those found in the binding motifs of RAS-interacting proteins or effectors and are often designed to form hydrogen bonds or other interactions with key residues on the surface of RAS. Peptide-based RAS(OFF) inhibitors that target other regions of the RAS protein are typically designed to disrupt other interactions that are critical for the activation or signaling of RAS. For example, some peptide-based inhibitors are designed to bind to the hypervariable region of RAS, which is thought to play a role in membrane localization and anchoring of the protein. By binding to this region, peptide- based inhibitors can prevent the proper localization of RAS to the plasma membrane, which is necessary for its activation and signaling. Several common motifs have been identified as important for the binding of RAS-interacting proteins and effectors and are often used in the design of peptide-based inhibitors. One example is the RAF-binding domain (RBD), which is found in many RAS-interacting proteins and is important for the interaction of RAS with downstream effectors such as RAF. The RBD contains a conserved amino acid sequence (Arg-Xaa-Arg) that is critical for binding to RAS, and this motif has been incorporated into several peptide-based inhibitors designed to disrupt the RAS-RAF interaction. Another example is the RAS-binding domain (RBD) of PI3K, which is important for the interaction of RAS with this downstream effector. The RBD of PI3K contains several conserved amino acid residues (such as Arg-Arg-Trp) that are critical for binding to RAS, and these motifs have been used in the design of peptide-based inhibitors that target the RAS-PI3K interaction. Other common motifs used in peptide-based RAS(OFF) inhibitors include the Ras-binding domain (RBD) of other RAS-interacting proteins such as RalGDS and SOS, as well as sequences that mimic the structure of the switch regions of RAS itself. These motifs are typically used to optimize the binding affinity and selectivity of the inhibitor for the desired target protein or interaction. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In some embodiments, the RAS(OFF) inhibitor is an antibody or antigenic binding peptide specific for RAS(OFF). Antibodies have been developed that bind to specific regions of the RAS protein, such as the Switch II region or the RAS-effector interface. For example, some antibodies have been developed that target the switch regions of RAS proteins, which are critical for the activation of these proteins and their interaction with downstream effectors. Binding of these antibodies to the switch regions can prevent the conformational changes required for RAS activation and downstream signaling. Another approach involves the use of antibodies that target RAS-interacting proteins or downstream effectors, such as RAF or PI3K. Binding of these antibodies to their target proteins can disrupt the RAS-dependent signaling pathways and inhibit the growth and survival of cancer cells. Additionally, some antibodies have been developed that can induce the internalization and degradation of RAS proteins, leading to their depletion and inhibition of downstream signaling. For example, some antibodies have been developed that recognize the unique structure of mutant RAS proteins and target them for degradation via the ubiquitin- proteasome pathway. Non-limiting examples of KRAS(OFF)-specific inhibitory antibodies include anti- p21ser, and K27 (DARPin) (see, e.g., Khan et al, Biochim Biophys Acta Mol Cell Res.2020 Feb;1867(2):118570). See also WO 2024136608 and WO 2024111590, each of which is incorporated herein by reference in its entirety. Antibody-drug conjugates may also be constructed using RAS inhibitors (e.g., RAS(OFF) inhibitors), such as WO 2024189481, which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. Vaccines may also be used in combination with compounds of the present invention. Non-limiting examples include: AFNT-111 (KRAS G12V), AFNT-211 (KRAS G12V), AFNT-212 (KRAS G12D), ELI- 002 (KRAS G12 / 13X), HB-700, NT-112 (KRAS G12D), and TG01 (pan-KRAS). Other RAS modalities useful in combination with compounds of the present invention include: ADGN-123, ADGN-121 (gene editing peptide-RNA nanoparticles G12D); ADT-030 (Ras / B-catenin inhibitor); BBO-10203 (PI3Kα:RAS breaker); BI 1701963 (pan-KRAS:SOS1); mRNA-5671 (nucleic acid) and RO7673396 (RAS inhibitor). ii) SOS1 inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more SOS1 inhibitors. A SOS1 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a SOS1 inhibitor is one or more of RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-1918455, BI-3406, SDR5, MRTX-0902, ZG2001, and BAY-293. In some embodiments, reference to the term SOS1 inhibitor includes any such SOS1 inhibitor disclosed in any one of the following patent applications: WO 2025070947, WO 2025067316, WO 2025062157, WO 2025059046, WO 2025038785, WO 2025003694, WO 2025000265, WO 2024255827, WO 2024172632, WO 2024172631, WO 2024119028, WO 2024102952, WO 2024083257, WO 2024083255, WO 2024079252, WO 2024075070, WO 2024067744, WO 2024035921, WO 2024027762, WO 2024008185, WO 2023250165, WO 2023215257, WO 2023215256, WO 2023180345, WO 2023109929, WO 2023059597, WO 2023041049, WO 2023029833, WO 2023022497, WO 2022184116, WO 2022171184, WO 2022170952, WO 2022170917, WO PATENT ATTORNEY DOCKET NO.: 51432-067WO2 2022170802, WO 2022161461, WO 2022157629, WO 2022139304, WO 2022121813, WO 2022028506, WO 2021228028, WO 2019122129, KR 20240128541, CN 119431234, CN 119039237, CN 119039234, CN 118812510, CN 117800922, CN117143175, CN 117143176, CN 116462669, CN 116444447, CN 115806560, CN 115677702, CN 115215847, CN 115028644, CN 114685488, and CN 111393519 each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iii) SHP inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more SHP inhibitors. A SHP inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, the SHP inhibitor is an inhibitor of SHP1. In some embodiments, the SHP inhibitor is an inhibitor of SHP2. In some embodiments, the SHP1 inhibitor is SB8091 or SB6299 aka DA-4511. In some embodiments, a SHP2 inhibitor is one or more of SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, ARRY-558, or BBP-398. In some embodiments, reference to the term SHP2 inhibitor includes any such SHP2 inhibitor disclosed in any one of the following patent applications: WO 2025075693, WO 2025019666, WO 2025011568, WO 2025011480, WO 2024258652, WO 2024193439, WO 2024175081, WO 2024147703, WO 2024125603, WO 2023282702, WO 2023280283, WO 2023280237, WO 2023018155, WO 2023011513, WO 2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO 2022242767, WO 2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO 2022235822, WO 20222084008, WO 2022135568, WO 2022063190, WO 2022043865, WO 2022042331, WO 2022033430, WO 2022017444, WO 2022007869, WO 2021259077, WO 2021249449, WO 2021249057, WO 2021244659, WO 2021218755, WO 2021176072, WO 2021171261, WO 2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO 2021143680, WO 2021281752, WO 2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO 2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO 2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO 2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO 2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO 2020156242, WO 2020108590, WO 2020104635, WO 2020094104, WO 2020094018, WO 2020081848, WO 2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO 2020065452, WO 2020063760, WO 2020061103, WO 2020061101, WO 2020033828, WO 2020033286, WO 2020022323, WO 2019233810, WO 2019213318, WO 2019183367, WO 2019183364, WO 2019182960, WO 2019167000, WO 2019165073, WO 2019158019, WO 2019152454, WO 2019051469, WO 2019051084, WO 2018218133, WO 2018172984, WO 2018160731, WO 2018136265, WO 2018136264, WO 2018130928, WO 2018129402, WO 2018081091, WO 2018057884, WO 2018013597, WO 2017216706, WO 2017211303, WO 2017210134, WO 2017156397, WO 2017100279, WO 2017079723, WO 2017078499, WO 2016203406, WO 2016203405, WO 2016203404, WO 2016196591, WO 2016191328, WO 2015107495, WO 2015107494, WO 2015107493, WO 2014176488, WO 2014113584, CN 116332908, CN 119264153, CN 117069698, CN 117143107, CN 115677661, CN 115677660, CN PATENT ATTORNEY DOCKET NO.: 51432-067WO2 115611869, CN 115521305, CN 115490697, CN 115466273, CN 115394612, CN 115304613, CN 115304612, CN 115300513, CN 115197225, CN 114957162, CN 114920759, CN 114716448, CN 114671879, CN 114539223, CN 114524772, CN 114213417, CN 114195799, CN 114163457, CN 113896710, CN 113248521, CN 113248449, CN 113135924, CN 113024508, CN 112920131, CN 112823796, CN 112409334, CN 112402385, CN 112174935, 111848599, CN 111704611, CN 111393459, CN 111265529, CN 110143949, CN 108113848, US 11179397, US 11044675, US 11034705, US 11033547, US 11001561, US 10988466, US 10954243, US 10934302, or US 10858359, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iv) MEK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more MEK inhibitors. A MEK inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a MEK inhibitor is one or more of pimasertib, IMM-1-104, selumetinib, cobimetinib (COTELLIC®), trametinib (MEKINIST®), and binimetinib (MEKTOVI®). In some embodiments, a MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a Class II MEK1 mutation selected from ΔE51-Q58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N. In some embodiments, reference to the term MEK inhibitor includes any such MEK inhibitor disclosed in any one of the following patent applications: WO 2022221866, WO 2022125941, WO 2022208391, WO 2022015736, WO 2022177557, WO 2021018866, WO 2021069486, WO 2021142144, WO 2021168283, WO 2021234097, WO 2019076947, WO 2018233696, WO 2016188472, WO 2014063024, WO 2013019906, WO 2011047238, WO 2007044515, US 2023032403, and CN 115813930, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. v) RAF inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more RAF inhibitors. A RAF inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a RAF inhibitor is VS-6766 or BTDX-4933. In some embodiments, a RAF inhibitor is a BRAF inhibitor. BRAF inhibitors that may be used in combination with a RAS(ON) multi-selective inhibitor of the present disclosure include, for example, VS-6766, IK-595, vemurafenib, dabrafenib, and encorafenib. BRAF may comprise a Class 3 BRAF mutation. In some embodiments, the Class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E. In some embodiments, reference to the term RAF inhibitor includes any such RAF inhibitor disclosed in any one of the following patent applications: WO 2023076991, WO 2022226626, WO 2022226261, WO 2019084459, WO 2018203219, WO 201851306, WO 2017212442, WO 2015075483, PATENT ATTORNEY DOCKET NO.: 51432-067WO2 WO 2013134243, WO 2013134298, WO 2011047238, WO 2011025965, WO 2011025947, WO 2011025951, WO 2011025940, WO 2011025938, WO 2010065893, WO 2009016460, WO 2009130015, WO 2009111278, WO 2009111279, WO 2008028141, and WO 2006024834, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. vi) ERK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more ERK inhibitors. An ERK inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, an ERK inhibitor is an ERK1 / 2 inhibitor, such as ERAS-007. In some embodiments, an ERK inhibitor is an ERK 5 inhibitor. In some embodiments, an ERK inhibitor is one or more of ASTX-029 or I-75. In some embodiments, reference to the term ERK inhibitor includes any such ERK inhibitor disclosed in any one of the following patent applications: WO 2023076305, WO 2022259222, WO 2022221547, WO 2021110169, WO 2021110168, WO 2021252316, WO 2020102686, WO 2020228817, WO 2020107987, WO 2019233456, WO 2019233457, WO 2016025561, WO 2016192063, WO 2016106029, WO 2016106009, WO 2015051341, WO 2014124230, WO 2014052563, WO 2011041152, WO 200910550, WO 2008153858, CN114315837, CN 115057860, CN 107973783, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. vii) MAPK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Mitogen-Activated Protein Kinase (MAPK) inhibitors. A MAPK inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a MAPK inhibitor is a p38MAPK inhibitor or a MAP3K8 inhibitor. In some embodiments, the MAPK inhibitor is one or more of Tilpisertib (GS-4875) and neflamapidmod (VX-745). In some embodiments, reference to the term MAPK inhibitor includes any such MAPK inhibitor disclosed in any one of the following patent applications: WO 2016029263, CN 114767674, CN 115850179, and CN 1743006, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, a therapeutic agent that may be combined with a RAS(ON) inhibitor of the present disclosure is an inhibitor of MAP2K4. A non-limiting example of a MAP2K4 inhibitor useful according to the disclosure is HRX-0233. b) Kinase Inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more kinase inhibitors. Tyrosine kinases and serine / threonine kinases play a crucial role in various cellular processes such as cell signaling, growth, and differentiation. Kinase inhibitors known in the art have been developed as a treatment for various types of cancer in PATENT ATTORNEY DOCKET NO.: 51432-067WO2 addition to therapies for conditions such as neurodegenerative diseases, autoimmune disorders, and inflammation. i) PKA inhibitors In some embodiments, compositions and methods described herein may include one or more Protein Kinase A (PKA) inhibitors. A PKA inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a PKA inhibitor is H89. In some embodiments, reference to the term PKA inhibitor includes any such PKA inhibitor disclosed in any one of the following patent applications: CN 106620678 and CN 114632155, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. ii) FAK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Focal Adhesion Kinase (FAK) inhibitors. A FAK inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a FAK inhibitor is one or more of BI853520, defactinib, GSK2256098, PF-00562271, and VS-4718. In some embodiments, reference to the term FAK inhibitor includes any such FAK inhibitor disclosed in any one of the following patent applications: WO 2022152315, WO 2021098679, WO 2020135442, WO 2020191448, WO 2012022408, WO 2013134353, WO 2012110774, WO 2010062578, CN 111072571, and KR 101691536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iii) ROCK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Rho-associated, coiled-coil containing protein kinase (ROCK) inhibitors. A ROCK inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a ROCK inhibitor is GSK269962A. In some embodiments, reference to the term ROCK inhibitor includes any such ROCK inhibitor disclosed in any one of the following patent applications: WO 2023051753, WO 2022237892, WO 2022012409, WO 2021093795, WO 2021214200, WO 2020177292, WO 202011751, WO 2019014304, WO 2019179525, WO 2019089868, WO 2019014300, WO 2018108156, WO 2018009627, WO 2018009625, WO 2018009622, WO 2017123860, WO 2017205709, WO 2016112236, WO 2014068035, WO 2013030367, WO 2012146724, WO 2012067965, WO 2011107608, CN 108129453, CN 108191821, CN 110917352, CN 108558823, CN108047193, CN107973777, CN108047197, CN108129448, CN 115869304, and GB202214708, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 iv) MSK1 inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Mitogen- and stress-activated kinase (MSK1) inhibitors. A MSK1 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a MSK1 inhibitor is one or more of SB-747651A, SB 747651A, Ro 320432, CGP 57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, and AS601245. v) RSK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more ribosomal S6 kinase (RSK) inhibitors. A RSK1 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a RSK inhibitor is one or more of BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX 02565, LJI308, LJI308-S, LJI308-1, and LJH685-S. In some embodiments, a RSK inhibitor is PMD-026. In some embodiments, reference to the term RSK inhibitor includes any such RSK inhibitor disclosed in any one of the following patent applications: WO 2021249558, WO 2020165646, WO 2017141116, and CN 113801139, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. vi) ALK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Anaplastic Lymphoma Kinase (ALK) inhibitors. An ALK inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, an ALK inhibitor is one or more of Crizotinib (XALKORI®), Ceritinib (ZYKADIA®), Alectinib (ALECENSA®), Brigatinib (ALUNBRIG®), Lorlatinib (LORBRENA®), Ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (Ceritinib analog), CEP-37440; 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in examples 3-39 of WO05016894. In some embodiments, reference to the term ALK inhibitor includes any such ALK inhibitor disclosed in any one of the following patent applications: WO 2019142095, WO 2019179482, WO 2018130928, WO 2018127184, WO 2017101803, WO 2016192132, WO 2014100431, WO 2012082972, CN 111138492, CN 110526914, CN 109836415, CN 105801603, CN107987056, and CN 105878248, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. c) Receptor tyrosine kinase inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more receptor tyrosine kinase inhibitors. A receptor tyrosine kinase (RTK) inhibitor is a type of molecule (e.g., small molecule, antibody, and nucleic acid) that binds to and blocks the activity of receptor tyrosine kinases or their ligands. RTKs are proteins found on the surface of cells that play a critical role in cell signaling and growth and have been developed as therapeutics for a PATENT ATTORNEY DOCKET NO.: 51432-067WO2 range of diseases, including cancer, diabetes, and autoimmune disorders. In some embodiments, a therapeutic agent may be a pan-RTK inhibitor, such as afatinib. i) EGFR inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more EGFR inhibitors. An EGFR inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotide or siRNA. Useful antibody inhibitors of EGFR include cetuximab (ERBITUX®), panitumumab (VECTIBIX®), zalutumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti- EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res.1995, 1:1311-1318; Huang et al., 1999, Cancer Res.15:59(8):1935-40; and Yang et al., Cancer Res.1999, 59:1236-1243. The EGFR inhibitor can be monoclonal antibody Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof. Small molecule antagonists of EGFR include gefitinib (IRESSA®), Lazertinib, erlotinib (TARCEVA®), and lapatinib (TYKERB®). See, e.g., Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). In some embodiments, an EGFR inhibitor is one or more of cetuximab, gefitinib (IRESSA®), erlotinib (TARCEVA®), and afatinib (GILOTRIF®). Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. An EGFR inhibitor may be ERAS-801. In some embodiments, an EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4). In some embodiments, the EGFR inhibitor may be bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, ruxolitinib, sunitinib, vemurafenib, abrocitinib, asciminib, futibatinib, ibrutinib, imatinib, pacritinib, or sorafenib. In some embodiments, reference to the term EGFR inhibitor includes any such EGFR inhibitor disclosed in any one of the following patent applications: WO 2023041071, WO 2023049312, WO 2023020600, WO 2023284747, WO 2022206797, WO 2022258977, WO 2022033416, WO 2022033410, WO 2022105908, WO 2022100641, WO 2022014639, WO 2022007841, WO 2021018009, WO 2021057882, WO 2021252661, WO 2021018003, WO 2021073498, WO 2021238827, WO 2020254547, WO 2020216371, WO 2020147838, WO 2020207483, WO 2020254572, WO 2020001350, WO 2021001351, WO 2019164948, WO 2019218958, WO 2019046775, WO 2019015655, WO 2018121758, WO 2018218963, WO 2017220007, WO 2017205459, WO 2017161937, WO 2016192609, WO 199633980, WO 199630347, WO 199730034, WO 199730044, WO 199738994, WO 199749688, WO 199802434, WO 199738983, WO 199519774, WO 199519970, WO 199713771, WO 199802437, WO 199802438, WO 199732881, PATENT ATTORNEY DOCKET NO.: 51432-067WO2 WO 199833798, WO 199732880, WO 199732880, WO 199702266, WO 199727199, WO 199807726, WO 1997 / 34895, WO 199631510, WO 199814449, WO 199814450, WO 199814451, WO 199509847, WO 199719065, WO 199817662, WO 199935146, WO 199935132, WO 199907701, WO 199220642, DE 19629652, EP 682027, EP 837063, EP 0787772, EP 0520722, EP 0566226, CN 115960018, CN 110283162, CN 114044774, CN111973601, CN 111973602, and CN113896744, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. ii) HER2 inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more HER2 inhibitors. A HER2 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, an HER2 inhibitor is one or more of tucatinib, rastuzumab (HERCEPTIN™), pertuzumab (PERJECTA™), lapatinib (TYKERB™), ado-trastuzumab emtansine (KADCYLA™), and neratinib (NERLYNX™). Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (HERCEPTIN®) and pertuzumab (PERJECTA®); small molecule tyrosine kinase inhibitors such as gefitinib (IRESSA®), erlotinib (TARCEVA®), pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW- 572016; TYKERB®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ- 26483327. In some embodiments, reference to the term HER2 inhibitor includes any such HER2 inhibitor disclosed in any one of the following patent applications: WO 2021156178, WO 2021156180, WO 2021213800, WO 2021088987, WO 2013561183, and WO 2013056108, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iii) MET inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more MET inhibitors. A MET inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a MET inhibitor is one or more of Crizotinib (XALKORI™), Cabozantinib (Cometriq, CABOMETYX™), Capmatinib(TABRECTA™), Tepotinib (TEPMETKO™), Savolitinib (VOLITINIB™), Onartuzumab (METMAB™), Foretinib(GSK1363089), MGCD-265 (Amuvatinib), SU11274, and SU5416. In some embodiments, reference to the term MET inhibitor includes any such MET inhibitor disclosed in any one of the following patent applications: WO 2022226168, WO 2021222045, WO 2020047184, WO 2020015744, WO 2020244654, WO 2020156453, WO 2019206268, WO 2018077227, WO 2017012539, WO 2016015653, WO 2016012963, WO 2012015677, WO 2011162835, WO 2010089507, WO 2009091374, WO 2009056692, WO 2008051547, WO 2007130468, US 2012237524, CN 103497177, CN 107311983, CN 107382968, CN 110218191, and TW201331206, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 iv) AXL inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more AXL inhibitors. An AXL inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. AXL is a receptor tyrosine kinase that belongs to the TAM family of receptors, which also includes TYRO3 and MERTK. In some embodiments, an AXL inhibitor is one or more of bemcentib, BGB324, R428, SGI-7079, TP-0903, BMS- 777607, UNC2025, and TP-0903. In some embodiments, reference to the term AXL inhibitor includes any such AXL inhibitor disclosed in any one of the following patent applications: WO 2023045816, WO 2022237843, WO 2022246179, WO 2021012717, WO 2021088787, WO 2021067772, WO 2021239133, WO 2021204713, WO 2020238802, WO 2019039525, WO 2019101178, WO 2019074116, WO 2017146236, WO 2016097918, WO 2015012298, WO 2010005876, WO 2010083465, CN 115073367, and JP 2022171109, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. v) IGFR inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more insulin-like growth factor receptor 1 (IGF-1R) inhibitors. An IGFR inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. IGFR inhibitors have been developed to target the IGFR receptor, which plays a critical role in cancer progression and metastasis. In some embodiments, an IGFR inhibitor is one or more of linsitinib, AXL1717, OSI-906 (Linsitinib), BMS-754807, BI 836845, AZ12253801, PQIP (Pyrrolo[1,2-a]quinoxaline), and NVP-AEW541. In some embodiments, reference to the term IGFR inhibitor includes any such IGFR inhibitor disclosed in any one of the following patent applications: WO 2022115946, WO 2022217923, WO 2021203861, WO 2021246413, WO 2020116398, WO 2019046600, WO 2018195250, WO 2018221521, WO 2018204872, WO 2017072196, WO 2016173682, WO 2015162291, WO 2015162292, WO 2010066868, WO 2006069202, and CN 112125916, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. vi) RET inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Rearranged during transfection (RET) inhibitors. An RET inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. RET plays a critical role in various cellular processes, including cell growth, differentiation, survival, and migration. RET is activated by binding of its ligands, such as glial cell line-derived neurotrophic factor (GDNF) family ligands, which leads to the activation of downstream signaling pathways that promote these cellular processes. In some embodiments, a RET inhibitor is one or more of pralsetinib, selpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molidustat (BAY 85-3934), and RPI-1 (Retrophin). In some embodiments, reference to the term RET inhibitor includes any such RET PATENT ATTORNEY DOCKET NO.: 51432-067WO2 inhibitor disclosed in any one of the following patent applications: WO 2021211380, WO 2021057963, WO 2021043209, WO 2021222017, WO 2020035065, WO 2020114487, WO 2020200314, WO 2020200316, WO 2020114494, WO 2018071447, WO 2018213329, WO 2017079140, WO 2014050781, CN 113943285, CN 113683610, CN 113683611, CN 113620944, CN 113620945, CN 113527291, CN 113527292, CN 113527290, CN 113135896, CN 111057075, CN111233899, and CN111362923, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. vii) ROS1 inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more c-ros oncogene 1 (ROS1) inhibitors. A ROS1 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. ROS1 is a receptor tyrosine kinase that belongs to the insulin receptor family and plays a role in various cellular processes, including cell growth, differentiation, survival, and migration. In some embodiments, a ROS1 inhibitor is one or more of taletrectinib, DS-6051b, TPX-0131, GZD824, and PF-06463922. In some embodiments, reference to the term ROS1 inhibitor includes any such ROS1 inhibitor disclosed in any one of the following patent applications: WO 2021098703, WO 2020024825, and US 2017079972, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. viii) PDGFR inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more platelet-derived growth factor receptor (PDGFR) inhibitors. A PDGFR inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. PDGFR is a family of receptor tyrosine kinases that consists of two members, PDGFRα and PDGFRβ. They are activated by binding to their ligands, such as platelet-derived growth factor (PDGF), which leads to the activation of downstream signaling pathways that promote cell growth, proliferation, and survival. In some embodiments, a PDGFR inhibitor is one or more of CP-673451, imatinib, nintedanib (OFEV™), sunitinib (SUTENT™), pazopanib (VOTRIENT™), regorafenib (STIVARGA™), and dasatinib (SPRYCEL™). ix) FGF inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with fibroblast growth factor (FGF) inhibitors. An FGF inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. FGFRs are a family of receptor tyrosine kinases that consists of four members, FGFR1-4. FGFRs are activated by binding to their ligands, fibroblast growth factors (FGFs), which leads to the activation of downstream signaling pathways that promote cell growth, differentiation, and survival. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR2. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR4. In some embodiments, an FGFR inhibitor is one or more of futibatinib (TAK-659), erdafitinib (BALVERSA™), PATENT ATTORNEY DOCKET NO.: 51432-067WO2 infigratinib (TRUSELTIQ™), Debio 1347, and rogaratinib (BAY 1163877). In some embodiments, reference to the term FGFR inhibitor includes any such FGFR inhibitor disclosed in any one of the following patent applications: WO 2022033472, WO 2022152274, WO 2022166469, WO 2022206939, WO 2021037219, WO 2021089005, WO 2021113462, WO 2020185532, WO 2019213544, WO 2020164603, WO 2019154364, WO 2019034076, WO 2019213506, WO 2019223766, WO 2018028438, WO 2018153373, WO 2018121650, WO 2018010514, WO 2017028816, WO 2017118438, WO 2016134320, WO 2015008844, WO 2014172644, WO 2014007951, WO 2013179033, WO 2013087578, WO 2012047699, CN 105906630, CN 115869315, CN 115141176, CN 115043832, and CN 115028634, each of which is incorporated herein by reference in its entirety. In some embodiments, the FGF pathway inhibitor targets an FGF ligand. Such FGF pathway inhibitors include FGF ligand traps and antibodies. Non-limiting examples include, FP-1039, an FGF ligand trap consisting of the extracellular domain of FGFR1 fused to the Fc portion of human IgG1, designed to sequester FGF ligands and inhibit FGF signaling, and MFGR1877S, a monoclonal antibody targeting FGF ligands, designed to block FGF- mediated signaling, including the compound structures disclosed therein which are specifically incorporated herein by reference. x) VEGF inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more vascular endothelial growth factor (VEGF) signaling inhibitors. VEGF (vascular endothelial growth factor) signaling inhibitors are a class of drugs that target the signaling pathway mediated by VEGF and its receptors. VEGF plays a critical role in angiogenesis, the process of forming new blood vessels from existing ones, and it is overexpressed in many types of cancer, making it an attractive target for cancer therapy. A VEGF inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, the VEGF inhibitor is an antibody or antigen binding regions that specifically bind VEGF (e.g., bevacizumab), or soluble VEGF receptors or a ligand binding region thereof) such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto). In some embodiments, the VEGF inhibitor is one or more of bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, and pazopanib. d) PI3K / mTOR pathway inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more inhibitors of the PI3K-AKT-TOR signaling pathway. The PI3K- AKT-mTOR signaling pathway is a critical intracellular pathway that regulates a wide range of cellular processes including cell growth, proliferation, metabolism, and survival. The pathway is initiated when growth factors, such as insulin or IGF-1, bind to cell surface receptors and activate phosphoinositide 3- kinase (PI3K). Activated PI3K then phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates AKT. Activated AKT then phosphorylates a variety of downstream targets including the tuberous sclerosis complex (TSC1 / TSC2), leading to the activation of mTOR (mammalian target of rapamycin) complex 1 (mTORC1). Activated PATENT ATTORNEY DOCKET NO.: 51432-067WO2 mTORC1 promotes protein synthesis and cell growth by phosphorylating key regulators of translation initiation such as S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). i) PI3K inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more PI3K inhibitors. A PI3K inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. A PI3K inhibitor useful in a combination of the disclosure may be a PI3Kα:RAS breaker, such as BBO-10203. PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO 2006044453; 4-[2- (1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO 2009036082 and WO 2009055730); 2-methyl-2-[4- [3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO 2006122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7- methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO 2008070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl] phenol hydrochloride (available from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin- 3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]- thiazolidine-2,4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1- (phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrirnidin-4-one (available from Axon Medchem); XL-765; and XL- 147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136. In some embodiments, the PI3K inhibitor is alpelisib or copanlisib. In some embodiments, reference to the term PI3K inhibitor includes any such PI3K inhibitor disclosed in any one of the following patent applications WO 2025072451 A1, WO 2025061125 A1, WO 2025051235 A1, WO 2025045106 A1, WO 2025040167 A1, WO 2025036439 A1, WO 2025038698 A1, WO 2025038395 A1, WO 2025034858 A1, WO 2025034849 A1, WO 2025029683 A1, WO 2025016314 A1, WO 2025003330 A1, WO 2025007074 A1, WO 2025002179 A1, WO 2024260464 A1, WO 2024229121 A1, WO 2024222894 A1, WO 2024215799 A1, WO 2024192309 A1, WO 2024183806 A1, WO 2024182404 A1, WO 2024182447 A1, each of which is incorporated herein by reference in its entirety. ii) AKT inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more AKT inhibitors. An AKT inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. AKT inhibitors include, but are not limited to, ipatasertib, GSK-2141795, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J.2005, 385(Pt.2): 399-408); Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem. J.2005, 385(Pt.2): 399-408); API-59CJ- PATENT ATTORNEY DOCKET NO.: 51432-067WO2 Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05 / 011700); indole-3-carbinol and derivatives thereof (e.g., U.S. Pat. No.6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Suppl):3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res.2004, 10(15):5242-52); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res.2004, 64:4394-9). The PI3K / AKT inhibitor may include, but is not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758–1784. For example, the PI3K / AKT inhibitor may be selected from one or more of NVP- BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; and GSK2126458. iii) mTOR inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more mTOR inhibitors. A mTOR inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, e.g., PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and derivatives thereof, including: temsirolimus (TORISEL®); everolimus (AFINITOR®; WO 199409010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, e.g., as disclosed in WO 199802441 and WO 200114387, e.g. AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3- hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolyt)- rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin; derivatives disclosed in WO 2005005434; derivatives disclosed in U.S. Patent Nos.5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and in WO 1994090101, WO 199205179, WO 1993111130, WO 199402136, WO 199402485, WO 199514023, WO 199402136, WO 199516691, WO 199641807, WO 199641807, and WO 2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO 2005016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO 2018204416, WO 2019212990 and WO 2019212991), such as RMC-5552. iv) MNK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more mitogen-activated protein kinase- interacting kinase (MNK) inhibitors. A MNK inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. MNK proteins are activated downstream of the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a critical role in the regulation of cellular proliferation, differentiation, and survival. MNKs phosphorylate eIF4E, a key component of the eukaryotic translation initiation complex, which enhances the translation of specific mRNAs, including those encoding proteins involved in cell cycle regulation and oncogenesis. In some embodiments, a MNK inhibitor is one or more tomivosertib (eFT508), CGP57380, and SEL201. In some embodiments, reference to the term MNK inhibitor includes any such MNK inhibitor disclosed in any one of the following patent applications: WO PATENT ATTORNEY DOCKET NO.: 51432-067WO2 2021098691, WO 2020108619, WO 2020086713, WO 2018152117, WO 2018228275, WO 2015200481, and CN115583942, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. v) eIF4 inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more eukaryotic initiation factor 4A (eIF4A) inhibitors. An eIF4A inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. eIF4A is a critical component of the eukaryotic translation initiation complex, where it functions as an RNA helicase to unwind the secondary structure of mRNA and facilitate ribosome binding. eIF4A is required for the translation of many cancer-associated genes, making it an attractive therapeutic target for cancer treatment. In some embodiments, an eIF4A inhibitor is one or more zotatifin (eFT226), silvestrol, pateamine A, and rocaglates. In some embodiments, reference to the term eIF4A inhibitor includes any such eIF4A inhibitor disclosed in any one of the following patent applications: WO 2023034813, WO 2021195128, and WO 2017091585, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, compositions and methods described herein may include one or more eukaryotic initiation factor 4G (eIF4G) inhibitors. An eIF4G inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor of the present disclosure and / or any additional therapeutic agent described herein. eIF4G family includes several proteins that are involved in the initiation of protein translation. eIF4G serves as a scaffold for other proteins, including eIF4E and eIF4A, to form the eIF4F complex, which is responsible for binding to the 5’ cap of mRNA and unwinding the secondary structure of the mRNA to allow ribosomal scanning and translation initiation. In some embodiments, an eIF4G inhibitor is one or more pateamine A, and hippuristanol. e) DNA Damage Response Inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more DNA damage response (DDR) inhibitors. The DDR pathway is a critical cellular pathway that is activated in response to DNA damage and is essential for maintaining genomic stability, thereby preventing the development of cancer. However, cancer cells often have defects in the DDR pathway, which makes them more sensitive to DDR inhibitors. DDR inhibitors have shown promise in preclinical studies as potential cancer therapeutics, particularly in combination with other agents. i) Wee1 inhibitors In some embodiments, compositions and methods described herein may include one or more Wee1 inhibitors. A Wee1 inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor of the disclosure and / or any additional therapeutic agent described herein. Wee1 is a kinase that plays a critical role in regulating the cell cycle by inhibiting the activity of cyclin-dependent kinases (CDKs) and preventing the progression of cells through the G2 / M checkpoint. Wee1 is overexpressed in several cancer types and has been implicated in tumor growth and survival. In some embodiments, a Wee1 PATENT ATTORNEY DOCKET NO.: 51432-067WO2 inhibitor is one or more of imp7068, adavosertib, or ZNL-02-096. In some embodiments, reference to the term Wee1 inhibitor includes any such Wee1 inhibitor disclosed in any one of the following patent applications: WO 2022011391, WO 2022247641, WO 2021043152, WO 2020221358, WO 2020083404, WO 2020192581, WO 2019085933, WO 2018133829, WO 2015115355, WO 2015183776, WO 2014085216, and CN 114831993, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. ii) CHK inhibitors In some embodiments, compositions methods described herein may include one or more checkpoint kinase (CHK) inhibitors. A CHK inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the disclosure and / or any additional therapeutic agent described herein. CHK1 kinase is a critical regulator of the cell cycle and the DNA damage response pathway. In some embodiments, the CHK inhibitor is a CHK1 inhibitor. In some embodiments, a CHK inhibitor is a CHK2 inhibitor. In some embodiments, a CHK1 inhibitor is one or more BBI-355, rabusertib, LY2606368, LY2880070, GDC-0575, MK-8776, BEBT-260, and PEP07. In some embodiments, reference to the term CHK1 inhibitor includes any such CHK1 inhibitor disclosed in any one of the following patent applications: WO 2024196923, WO 2024211271, WO 2024211270, WO 2024118564, WO 2023230477, WO 2022251502, WO 2021113661, WO 2021104461, WO 2019012030, WO 2010118390, WO 2008067027, WO 2002070494, CN119661557, and TW202126818, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iii) ATM inhibitors In some embodiments, compositions and methods described herein may include one or more ataxia telangiectasia mutated (ATM) inhibitors. An ATM inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor of the disclosure and / or any additional therapeutic agent described herein. ATM plays a role in regulating the replication stress response and maintaining genomic stability. In some embodiments, an ATM inhibitor is one or more lartesertib , AZD1390, AZD0156, KU-60019, M4076, M3541, WSD-0628, ZN-B-2262, SYH2051, and VE-821. In some embodiments, reference to the term ATM inhibitor includes any such ATM inhibitor disclosed in any one of the following patent applications: WO 2024189299, WO 2022058351, WO 2021197339, WO 2021098734, WO 2021260580, WO 2020193660, WO 2020063855, WO 2016155884, WO 2007026157, WO 2006085067, US 2016113935, CN 116440082, CN 117180432 and CN 115105596 each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iv) ATR inhibitors In some embodiments, compositions and methods described herein may include one or more ataxia telangiectasia and Rad3-related (ATR) inhibitors. An ATR inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor of the disclosure and / or any additional therapeutic agent described herein. In some embodiments, an ATR inhibitor is one or more berzosertib, gartisertib, camonsertib, ceralaertib, VE-821, RP-3500, AZ20, VX-970, abd110, VX-803, and elimusertib (BAY PATENT ATTORNEY DOCKET NO.: 51432-067WO2 1895344). In some embodiments, reference to the term ATR inhibitor includes any such ATR inhibitor disclosed in any one of the following patent applications: WO 2025019344, WO 2025019346, WO 2023138343, WO 2023126823, WO 2023109883, WO 2023016529, WO 2022237875, WO 2022268025, WO 2021012049, WO 2021023272, WO 2021260579, WO 2021228758, WO 2019050889, WO 2019154365, WO 2019036641, WO 2019133711, WO 2017059357, WO 2013049859, WO 2007046426, WO 2007015632, and CN113797341, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. v) PARP inhibitors In some embodiments, compositions and methods described herein may include one or more Poly(ADP-ribose) polymerase (PARP) inhibitors. A PARP inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the disclosure and / or any additional therapeutic agent described herein. There are 17 PARP (aka tankyrase) family members that have been identified. PARP enzymes play a critical role in DNA damage repair, particularly in the repair of single-strand DNA breaks. PARP inhibitors block the activity of PARP enzymes, leading to the accumulation of DNA damage and ultimately cell death. In some embodiments, a PARP inhibitor is one or more olaparib, rucaparib, niraparib, and veliparib (ABT-888). In some embodiments, reference to the term PARP inhibitor includes any such PARP inhibitor disclosed in any one of the following patent applications: WO 2025024581, WO 2025037273, WO 2025061057, WO 2024256377, WO 2024255782, WO 2023051812, WO 2023051807, WO 2023051716, WO 2023278592, WO 2022228387, WO 2022022664, WO 2022000946, WO 2022222921, WO 2021163530, WO 2020122034, WO 2020239097, WO 2020142583, WO 2020156577, WO 2020098774, WO 2020196712, WO 2019200382, WO 2018125961, WO 2018205938, WO 2018192576, WO 2018218025, WO 2017032289, WO 2017177838, WO 2017029601, WO 2017088723, WO 2016155655, WO 2015154630, WO 2013097225, WO 2012130166, WO 2011006794, WO 2009046205, WO 2009063244, WO 2008084261, WO 2007138351, WO 2006110816, WO 2005053662, WO 2005012524, CN113698356, CN 113603647, CN 115073544, CN 108938634, CN 104887680, CN 110343088, CN108976236, CN 117069731, CN 119185316, CN 119112794, and CN 107629071, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. vi) DNA-PK inhibitors In some embodiments, compositions and methods described herein may include one or more DNA-dependent protein kinase (DNA-PK) inhibitors. A DNA-PK inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor of the disclosure and / or any additional therapeutic agent described herein. DNA-PK is a serine / threonine protein kinase that plays a crucial role in DNA repair and maintenance of genome stability. In some embodiments, a DNA-PK inhibitor is one or more NU7441, AZD7648, VX-984, peposertib (M3814), and CC-115. In some embodiments, reference to the term DNA-PK inhibitor includes any such DNA-PK inhibitor disclosed in any one of the following patent applications: WO 2025023957, WO 2023220418, WO 2023215991, WO 2023165603, WO 2022187965, WO 2021197159, WO 2021260583, WO 2021204111, WO 2021104277, WO 2021098813, WO 2021022078, WO 2020259613, WO 2019143678, WO 2019143675, WO 2019201283, WO 2015058031, PATENT ATTORNEY DOCKET NO.: 51432-067WO2 WO 2014159690, WO 2012028233, WO 2009010761, WO 2006032869, WO 2006109084, CN 112574179, CN 112300132, CN 115322209, and CN 112300126, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. f) Cell Cycle Inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more cell cycle inhibitors. Cell cycle inhibitors target specific proteins involved in regulating the cell cycle, which is the process by which a cell divides and replicates its DNA. Non-limiting examples cell cycle proteins include cyclin-dependent kinase (CDK), aurora kinase, and polo-like kinase (PLK). CDKs are a family of kinases that are involved in regulating the cell cycle. CDK inhibitors block the activity of these kinases, leading to cell cycle arrest and / or apoptosis. Aurora kinases are a family of serine / threonine kinases that play a critical role in regulating mitosis. Aurora kinase inhibitors block the activity of these kinases, leading to mitotic arrest and cell death. PLKs are a family of serine / threonine kinases that are involved in regulating multiple stages of the cell cycle. PLK inhibitors block the activity of these kinases, leading to cell cycle arrest and / or apoptosis. i) CDK inhibitors In certain embodiments, a cell cycle inhibitor is a cyclin-dependent kinase (CDK) inhibitor. Cyclin- dependent kinases are a family of protein kinases that regulate cell division and proliferation. Cell cycle progression is controlled by cyclins and their associated cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4 and CDK6, while other CDKs such as CDK7, CDK8 and CDK9 are critical to transcription. CDK binding to cyclins forms heterodimeric complexes that phosphorylate their substrates on serine and threonine residues, which in turn initiates events required for cell-cycle transcription and progression. In some embodiments, a CDK inhibitor is a CDK2 inhibitor. In some embodiments, a CDK inhibitor is a CDK4 / 6 inhibitor. In some embodiments, a CDK inhibitor is a CDK7 inhibitor. In some embodiments, a CDK inhibitor is a CDK9 inhibitor. In some embodiments, a CDK inhibitor is one or more palbociclib, ribociclib, abemaciclib, and trilaciclib. In some embodiments, a CDK inhibitor is one or more of tagtociclib (PF-07104091), seliciclib, voruciclib (P1446A-05), BLU-222, dinaciclib, AT-7519, RGB286638, and AZD4573. In some embodiments, reference to the term CDK inhibitor includes any such CDK inhibitor disclosed in any one of the following patent applications: WO 2025040170, WO 2025060620, WO 2024238574, WO 2024027825, WO 2024048541, WO 2022166793, WO 2022187611, WO 2022130304, WO 2021227906, WO 2021057867, WO 2020207260, WO 2020138370, WO 2020125513, WO 2020093011, WO 2020148635, WO 2020215156, WO 2020052627, WO 2017177837, WO 2017162215, WO 2017177836, WO 2017172826, WO 2016193939, WO 2016014904, WO 2016015598, WO 2016015605, WO 2015181737, WO 2012061156 A1, WO 2012038411, WO 2010020675, WO 2010125004, WO 2007139732, WO 2006024945, CN 114478529, CN 108794496, CN 105294737, CN107652284, KR 20180106188, and US 2017152269, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 ii) Aurora kinase inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more aurora kinase inhibitors. An aurora kinase inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor of the present disclosure and / or any additional therapeutic agent described herein. Aurora kinases are a family of serine / threonine kinases that play a critical role in regulating cell division and maintaining genomic stability. The Aurora kinase family consists of three members: Aurora A, Aurora B, and Aurora C. In some embodiments, an aurora kinase inhibitor is one or more palbociclib, ribociclib, and abemaciclib. In some embodiments, an aurora kinase inhibitor is one or more of alisertib, danusertib, barasertib, and MLN8237. In some embodiments, reference to the term aurora kinase inhibitor includes any such aurora kinase inhibitor disclosed in any one of the following patent applications: WO 2021110009, WO 2021008338, WO 2020112514, WO 2019129234, WO 2016077161, WO 2013143466, WO 2011103089, WO 2010081881, WO 2010133794, WO 2009134658, WO 2008001886, WO 2007095124, WO 2007003596, WO 2006129064, CN 114276227, CN 108078991, CN 106543155, CN 104211692, and CN 104098551, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iii) PLK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more polo-like kinase (PLK) inhibitors. A PLK inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. PLKs are a family of serine / threonine kinases that play a crucial role in regulating cell division, DNA damage response, mitotic progression, and consists of four members: PLK1, PLK2, PLK3, and PLK4. In some embodiments, a PLK inhibitor is one or more of volasertib, onvansertib, BI 2536, and GSK461364. In some embodiments, reference to the term PLK inhibitor includes any such PLK inhibitor disclosed in any one of the following patent applications: WO 2011012534 A1, WO 2010065134, WO 2009130453, WO 2009042806, WO 2004043936, WO 2007030361, WO 2006021547, CN 115804777, and EP 2325185, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iv) Kinesin superfamily of microtubule motor protein inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Kinesin spindle protein (KSP) inhibitors. In some embodiments, compositions described herein may include one or more Kinesin family (KIF) inhibitors. In some embodiments, a KSP inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. KSP and KIF are a subset of the kinesin superfamily of microtubule motor proteins. KSP, also known as Eg5, is a member of the kinesin superfamily of motor proteins that plays a critical role in mitotic spindle formation and cell division. KSP inhibitors selectively target rapidly dividing cancer cells by disrupting spindle formation and inducing mitotic arrest. In some embodiments, a KSP inhibitor is one or more of SB743921, monastrol, S-Trityl-L-cysteine (STLC), and filanesib (ARRY-520). In some PATENT ATTORNEY DOCKET NO.: 51432-067WO2 embodiments, a KIF inhibitor is an inhibitor of a Kinesin-8 family microtubule motor protein. In some embodiments, the kinesin-8 family protein is KIF18A. In some embodiments, a KIF inhibitor is one or more of AMG650, BTB-1, K03861, and SJ000291942. In some embodiments, reference to the term kinesin superfamily of microtubule motor protein inhibitor includes any such kinesin superfamily of microtubule motor protein inhibitor disclosed in any one of the following patent applications: WO 2015114854, WO 2015114855, WO 2010084186, WO 2006101761, WO 2006110390, WO 2006044825, WO 2006078574, WO 2005060654, WO 2004092147, WO 2004037171, WO 2004058700, WO 2003050064, WO 2003105855, WO 2022037665, WO 2018114804, WO 2017162663, WO 2016207089, WO 2012073375, JP 2014162787, JP 2019189590, JP2013166713, and KR 20220145566, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. v) DYRK1 inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Dual-specificity tyrosine phosphorylation-regulated kinase 1 (DYRK1) inhibitors. A DYRK1 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. DYRK1 is a member of the DYRK (dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases. It plays essential roles in various cellular processes, including cell cycle regulation, neuronal development, and transcriptional control. In some embodiments, a DYRK1 inhibitor is one or more of harmine, INDY, D4476, and AZ191. In some embodiments, reference to the term DYRK1 inhibitor includes any such DYRK1 inhibitor disclosed in any one of the following patent applications: WO 2023277331 A1, WO 2023140846 A1, WO 2017181087 A1, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. g) Anti-Apoptotic Protein Inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more anti-apoptotic protein inhibitors. In some embodiments, an anti-apoptotic protein inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. Anti- apoptotic inhibitors target proteins that play a role in preventing apoptosis, a form of programmed cell death. Apoptosis is a critical mechanism for eliminating damaged or unwanted cells. Anti-apoptotic proteins are a family of proteins that inhibit the apoptotic pathway, thereby preventing cell death. There are several known classes of anti-apoptotic inhibitors, including Bcl-2 inhibitors, XIAP inhibitors, survivin inhibitors, Mcl-1 inhibitors, and FLIP inhibitors. These inhibitors work by binding to specific anti-apoptotic proteins and preventing their activity, thereby promoting cell death in cancer cells. In some embodiments, compositions described herein may include one or more anti-apoptotic protein inhibitors. An anti-apoptotic protein inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the disclosure and / or any additional therapeutic agent described herein. In some embodiments, the anti-apoptotic protein inhibitor includes a MCL-1 inhibitor. Non-limiting examples of MCL-1 inhibitors include, AMG-176, MIK665, and S63845. The myeloid cell leukemia-1 (MCL-1) protein is PATENT ATTORNEY DOCKET NO.: 51432-067WO2 one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263. In some embodiments, the anti-apoptotic protein inhibitor includes a BCL protein inhibitor. Examples of BCL protein inhibitors include but are not limited to Venetoclax (Venclexta), Navitoclax (ABT-263), A-1331852, S63845, and AT-101. h) Autophagy Inhibitors Compositions and methods described herein may include a RAS(ON inhibitor of the present disclosure in combination with one or more autophagy inhibitors. In some embodiments, an autophagy inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. Autophagy inhibitors include, but are not limited to chloroquine, 3- methyladenine, hydroxychloroquine (PLAQUENIL™), spautin-1, SAR405, bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagy- suppressive algal toxins which inhibit protein phosphatases of type 2A or type 1, analogues of cAMP, and drugs which elevate cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used. In some embodiments, the one or more additional therapies include an autophagy inhibitor. a) ULK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Unc-51-like kinase (ULK) inhibitors. An ULK inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a ULK inhibitor is a ULK1 / 2 inhibitor. In some embodiments, an ULK inhibitor is one or more of ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, and Dorsomorphin. b) VPS inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Vacuolar protein sorting protein (VPS) inhibitors. A VPS inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. VPS (proteins are a family of proteins that play a critical role in the process of autophagy by regulating the formation and function of autophagosomes, structures that engulf and transport cellular components to lysosomes for degradation. Dysregulation of VPS proteins has been implicated in various diseases, including cancer, neurodegenerative disorders, and infectious diseases. In some embodiments, a VPS inhibitor is a VPS34 inhibitor. In some embodiments, a VPS inhibitor is one or more of PIK-III, VPS34-IN1, SAR405, Spautin-1, and NSC185058. c) Macropinocytosis inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more macropinocytosis inhibitors. A PATENT ATTORNEY DOCKET NO.: 51432-067WO2 macropinocytosis inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the disclosure and / or any additional therapeutic agent described herein. Macropinocytosis inhibitors are compounds that can block or reduce the process of macropinocytosis. In some embodiments, a macropinocytosis inhibitor is one or more of EIPA (ethylisopropylamiloride), Wortmannin, Amiloride, Apilimod, Dyngo-4a, and Latrunculin B. i) WNT / β-catenin Pathway Inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more WNT / beta-catenin pathway inhibitors. In some embodiments, a WNT / beta-catenin pathway inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. The WNT / beta-catenin pathway is an important signaling pathway that plays a crucial role in development, tissue homeostasis, and disease. Dysregulation of this pathway has been implicated in various cancers, making it an attractive target for cancer therapy. WNT / beta-catenin pathway inhibitors target various components of the pathway, including WNT ligands, receptors, and downstream effectors. i) β-catenin inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure and one or more β-catenin inhibitors. A β-catenin inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. Beta-catenin is a protein that plays an important role in the WNT signaling pathway, which regulates various cellular processes including cell proliferation, differentiation, and migration. In normal cells, β-catenin levels are tightly regulated by a destruction complex, which marks beta-catenin for degradation. However, in many cancer cells, the destruction complex is impaired, leading to the accumulation of beta-catenin in the nucleus and the activation of target genes involved in tumor growth and metastasis. In some embodiments, a WNT / β- catenin inhibitor is one or more of FOG-001, OMP-131R10, Foxy-5, LGK974, RXC004, ETC-159, OMP- 54F28, Niclosamide, OMP-18R5, OTSA-101, BNC101, DKN-01, Sulindac, Pyrvinium, E7449, BC2059, PRI-724, SM08502, IWP1, IWP2, IWP3, IWP4, IWP12, IWP L6, C59, GNF-6231, GNF-1331, DK-520, DK-419, IgG-2919, Fz7-21, RHPD-P1, SRI37892, 1094-0205, 2124-0331, 3235-0367, NSC36784, NSC654259, IgG-2919, Salinomycin, BMD4702, 3289-8625, J01-017a, FJ9, KY-02061, KY-02327, NSC668036, Peptide Pen-N3, SSTC3, CCT031374, TCS 183, XAV939, AZ1366, G007-LK, MSC2504877, G244-LM, IWR-1, JW74, JW55, K-756, NVP-TNKS656, MN-64, RK-287107, WIKI4, KY1220, KYA1797K, MSAB, PKF115-584, CGP049090, AV-65, PNU-74654, Windorphen, IQ-1 tegavivant, foscenvivant, PNPB-29, ZW4864, SAH-BCL9, Carnosic acid, xStAx-VHL, NRX-252114, Septuximab vedotin, PF-06647020, LGR5-mc-vc-PAB-MMAE, LGR5-NMS818, CWP232291, PRI-724 (also known as ICG-001), C-82, and BC2059. In some embodiments, reference to the term β-catenin inhibitor includes any such β-catenin inhibitor disclosed in any one of the following patent applications: CN 104388427 and CN 103830211, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 ii) PORCN inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Porcupine (PORCN) inhibitors. A PORCN inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. PORCN is a membrane-bound O-acyltransferase enzyme that plays a critical role in the WNT signaling pathway by mediating the palmitoylation of WNT ligands. This palmitoylation is essential for the secretion and signaling activity of WMT proteins. Inhibition of PORCN leads to reduced WNT signaling activity. In some embodiments, a PORCN inhibitor is one or more of LGK974 (WNT974), ETC-1922159, CGX1321, and CWP232291. iii) GSK3 inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Glycogen synthase kinase (GSK3) inhibitors. A GSK3 inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. The GSK3 family consists of two closely related serine / threonine kinases: GSK3α and GSK3β. These kinases are involved in numerous cellular processes, including glycogen metabolism, cell cycle regulation, and Wnt signaling. GSK inhibitors have been investigated as potential therapeutics for various diseases, including cancer, diabetes, Alzheimer's disease, and bipolar disorder. In some embodiments, a GSK3 inhibitor is one or more of Tideglusib, laduviglusib, LiCl (Lithium chloride), CHIR99021, SB216763, AZD1080, and LY2090314. In some embodiments, reference to the term GSK3 inhibitor includes any such GSK3 inhibitor disclosed in any one of the following patent applications: WO 2017153834, WO 2014059383, WO 2010012398, WO 2009017455, WO 2003037891, CN 107151235, and CN 102258783, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iv) CLK inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) multi-selective inhibitor of the present disclosure in combination with one or more Cdc2-like kinase (CLK) inhibitors. A CLK inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. LKs (Cdc2-like kinases) are a family of serine / threonine kinases that play a crucial role in pre-mRNA splicing, specifically in the regulation of alternative splicing. There are four members of the CLK family: CLK1, CLK2, CLK3, and CLK4. The CLK family of kinases have been shown to be involved in several diseases, including cancer, neurodegenerative disorders, and viral infections. In some embodiments, a CLK inhibitor is a CLK 2 inhibitor. In some embodiments, a CLK2 inhibitor is one or more of Lorecivivint, SM08502, SM04690, TG003, KH-CB19, Cmpd-1, T3.5, and CX-4945. In some embodiments, reference to the term CLK inhibitor includes any such CLK inhibitor disclosed in WO 2020006115, which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 j) JAK / STAT Pathway Inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more JAK / STAT pathway inhibitors. In some embodiments, a JAK / STAT pathway inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. The Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway is a signaling pathway involved in many cellular processes, including immune response, cell growth, and differentiation. Dysregulation of this pathway has been linked to various diseases, including inflammatory disorders, cancer, and autoimmune diseases. Inhibitors of the JAK / STAT pathway can be used for the treatment of these diseases. In some embodiments, a JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2 and / or JAK3. In some embodiments, a JAK inhibitor is one or more of Ruxolitinib (JAKAFI®), Pacritinib, Fedratinib, Tofacitinib (XELJANZ®), Abrocitinib, Filgotinib, Oclacitinib, Peficitinib, Upadacitinib, Deucravacitinib, Delgocitinib, and Baricitinib (OLUMIANT®). In some embodiments, reference to the term JAK inhibitor includes any such JAK inhibitor disclosed in any one of the following patent applications: WO 2023011301, WO 2023201044, WO 2022143629, WO 2022251434, WO 2022067106, WO 2022033551, WO 2021244323, WO 2021238817, WO 2021238818, WO 2021178991, WO 2021136345, WO 2021190647, WO 2020219639, WO 2020182159, WO 2020155931, WO 2020038457, WO 2020219524, WO 2020173400, WO 2018204233, WO 2018204238, WO 2018169875,WO 2018117152, WO 2017215630, WO 2016070697, WO 2016027195, CN 117815195, CN117815367, and CN 115969796, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, the JAK / STAT pathway inhibitor is a STAT inhibitor. In some embodiments, the STAT inhibitor is an inhibitor of STAT3 and / or STAT5. In some embodiments, the STAT inhibitor is a STAT3 degrader. In some embodiments, the STAT3 degrader is KT-333. In some embodiments, the STAT inhibitor is one or more of TTI-101, C-188-9, WP1066, VVD-130850, LLL12B, STA-21, SD-36, Stattic, S3I-201, OPB-31121, KT-333, and Napabucasin (BBI608). In some embodiments, reference to the term STAT inhibitor includes any such STAT inhibitor disclosed in any one of the following patent applications: WO 2024030628, WO 2023164680, WO 2023192960, WO 2023133336, WO2020206424, WO 2023107706, WO 2021150543, WO 2008151037, and CN 109288845, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. k) Epigenetic Modulators Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more epigenetic modulators. Epigenetic modulators are a class of therapeutics that target enzymes responsible for modifying the structure and function of chromatin, the complex of DNA and proteins that make up chromosomes. These enzymes, including histone deacetylases (HDACs), histone methyltransferases (HMTs), and DNA methyltransferases (DNMTs), play critical roles in gene expression and regulation by modifying the packaging of DNA and affecting how it is read and transcribed. Epigenetic modulators work by altering the activity of these enzymes, either by inhibiting or enhancing their function, to regulate gene expression in specific ways. By targeting specific PATENT ATTORNEY DOCKET NO.: 51432-067WO2 epigenetic modifications, such as acetylation, methylation, and DNA methylation, these therapies have the potential to treat a wide range of diseases, including cancer, inflammatory disorders, and neurological disorders. i) HDAC inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more histone deacetylase (HDAC) inhibitors. A HDAC inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. There are several classes of HDACs, including class I, class IIa, class IIb, class III, and class IV. Class I HDACs are further divided into HDAC1, HDAC2, HDAC3, and HDAC8, while class IIa HDACs include HDAC4, HDAC5, HDAC7, and HDAC9. Class IIb HDACs consist of HDAC6 and HDAC10, and class III HDACs are known as sirtuins. HDAC inhibitors can target different classes of HDACs, and their specific effects on gene expression can vary depending on which HDACs they target. In some embodiments, a HDAC inhibitor is one or more of Vorinostat (ZOLINZA™), Romidepsin (ISTODAX™), Belinostat (BELEODAQ™), Panobinostat (FARYDAK™), Entinostat (MS-275), Valproic acid (DEPAKENE™), Trichostatin A (TSA), Sodium butyrate, and Mocetinostat (MGCD0103). Non-limiting examples of HDAC inhibitors include trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and Panobinostat. In some embodiments, reference to the term HDAC inhibitor includes any such HDAC inhibitor disclosed in any one of the following patent applications: WO 2022110958, WO 2021252628, WO 2019204550, WO 2018178060, WO 2016126724, WO 2014143666, WO 2013041480, and WO 2006120456, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. ii) BET inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more bromodomain and extra-terminal protein (BET) inhibitors. A BET inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. BET (bromodomain and extra-terminal) proteins are a family of epigenetic reader proteins that recognize and bind to acetylated lysine residues on histones, leading to chromatin remodeling and gene expression regulation. There are four BET proteins in humans: BRD2, BRD3, BRD4, and BRDT. BET inhibitors specifically target the bromodomains of BET proteins, inhibiting their binding to acetylated lysine residues on histones and leading to alterations in gene expression. BET inhibitors are useful in the treatment of cancer and other diseases characterized by dysregulated gene expression. In some embodiments, a BET inhibitor is one or more of JQ1, I-BET762, OTX015, RVX-208, and CPI-0610. In some embodiments, reference to the term BET inhibitor includes any such BET inhibitor disclosed in any one of the following patent applications: WO 2022046682, WO 2022182857, WO 2021107657, WO 2021107656, WO 2020221006, WO 2020053660, WO 2018097977, WO 2017222977, WO 2017142881, WO 2015075665, WO 2015011084, and CN 113264930, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 iii) EZH2 inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) multi-selective inhibitor of the present disclosure in combination with one or more Enhancer of Zeste Homolog 2 (EZH2) inhibitors. An EZH2 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. EZH2 is a histone-lysine N-methyltransferase that is a member of the Polycomb repressive complex 2 (PRC2) family. EZH2 plays a crucial role in gene expression regulation, specifically by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), leading to transcriptional repression of target genes. EZH2 has been found to be overexpressed in several types of cancers and is associated with tumor progression and poor prognosis. In some embodiments, an EZH2 inhibitor is one or more of Tazemetostat, GSK2816126, and CPI-1205 (lirametostat). In some embodiments, reference to the term EZH2 inhibitor includes any such EZH2 inhibitor disclosed in any one of the following patent applications: WO 2023030299, WO 2022179584, WO 2020224607, WO 2021243060, WO 2021086069, WO 2019206155, WO 2018133795, WO 2018137639, WO 2017184999, WO 2017218953, WO 2016201328, WO 2015195848, WO 2013155317, WO 2013138361, and CN 114621191, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iv) Co-REST inhibitors In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Co-REST inhibitors. A Co-REST inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. Co-REST is a transcriptional co-repressor protein that interacts with a variety of transcription factors to regulate gene expression. Co- REST acts by recruiting histone deacetylases (HDACs) to chromatin, leading to the repression of gene expression. Inhibition of Co-REST has been proposed as a potential therapeutic strategy for the treatment of various diseases, including neurodegenerative disorders and cancer. In some embodiments, a co-REST inhibitor is one or more of Nocodazole, NSC 1892, and Anacardic acid. v) EP300 In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more E1A-binding protein p300 (EP300) inhibitors. An EP300 inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. EP300 is a transcriptional co-activator involved in the regulation of numerous cellular processes, including chromatin remodeling, DNA damage response, and cell cycle progression. EP300 acts as a histone acetyltransferase, catalyzing the transfer of acetyl groups to lysine residues on histone proteins, which leads to changes in chromatin structure and gene expression. EP300 activity has been implicated in diseases, such as cancer, cardiovascular and neurological disorders. In some embodiments, an EP300 inhibitor is one or more of C646, A-485, NU9056, and L002. In some embodiments, reference to the term EP300 inhibitor includes any such EP300 inhibitor disclosed in any one of the following patent applications: WO 2021213521 and WO 2016044694, each of which is incorporated herein by reference in PATENT ATTORNEY DOCKET NO.: 51432-067WO2 its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. vi) LSD1 In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Lysine-specific demethylase 1 (LSD1) inhibitors. A LSD1 inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. LSD1 is an enzyme that plays a crucial role in regulating gene expression through histone modification. It specifically removes the methyl group from lysine 4 on histone 3, leading to gene repression. Dysregulation of LSD1 has been associated with various diseases including cancer and neurodegenerative disorders. In some embodiments, a LSD1 inhibitor is one or more of GSK2879552, IMG-7289, ORY-1001, IMG-8419, SP-2577, CC-90011, HCI-2509, and INCB059872. In some embodiments, reference to the term LSD1 inhibitor includes any such LSD1 inhibitor disclosed in any one of the following patent applications: WO 2021095840, WO 2021175079, WO 2021058024, WO 2020047198, WO 2020052649, WO 2020015745, WO 2020052647, WO 2018137644, WO 2017184934, WO 2017027678, WO 2017116558, WO 2017149463, WO 2016161282, WO 2015123465, WO 2015123424, WO 2013057322, WO 2013057320, WO 2012135113, CN 114805261, CN 111072610 CN107174584, CN 110478352, CN 106432248, and CN 106045881, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. vii) PRMT5 In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Protein arginine methyltransferase 5 (PRMT5) inhibitors. A PRMT5 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. PRMT5 is a member of the PRMT family, which catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the nitrogen atoms of arginine residues in target proteins. PRMT5 is involved in various biological processes, including gene expression regulation, signal transduction, and DNA repair. In some embodiments, a PRMT5 inhibitor is one or more of TNG908, TNG462, AMG193, GSK591, EPZ015666, TC-E 5003, and MS023. In some embodiments, reference to the term PRMT5 inhibitor includes any such PRMT5 inhibitor disclosed in any one of the following patent applications: WO 2023001133, WO 2022206964, WO 2022153161, WO 2021068953, WO 2021088992, WO 2020259478, WO 2020205660, WO 2020250123, WO 2020033288, WO 2019102494, WO 2019112719, WO 2019180631, WO 2018065365, WO 2017153186, WO 2017212385, WO 2017032840, WO 2016022605, WO2014100695, WO 2014145214, WO 2014100719, CN 111825656, CN 114558014, CN 11304554, and CN 112778275, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 viii) MAT2A In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more methionine adenosyltransferase 2A (MAT2A) inhibitors. A MAT2A inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. MAT2A is an enzyme that catalyzes the production of S-adenosylmethionine (SAM), which is an important cofactor in many biological processes, including DNA methylation, protein methylation, and polyamine synthesis. Elevated MAT2A expression has been associated with various cancers. In some embodiments, a MAT2A inhibitor is one or more of cycloleucine and 2-hydroxy-4-methylthiobutanoic acid. In some embodiments, reference to the term MAT2A inhibitor includes any such MAT2A inhibitor disclosed in any one of the following patent applications: WO 2022256808, WO 2022256806, WO 2019191470, and CN 115716831, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. ix) DOT1L In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Disruptor of Telomeric silencing 1-like (DOT1L) inhibitors. A DOT1L inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. DOT1L is a histone methyltransferase enzyme that catalyzes the methylation of lysine 79 on histone H3. This modification is associated with transcriptional elongation and is important for the maintenance of gene expression programs. The DOT1L family includes enzymes that are involved in epigenetic regulation and transcriptional control, and their dysregulation has been linked to various diseases, including cancer. In some embodiments, a DOT1L inhibitor is one or more of EPZ-5676 (pinometostat) and EPZ-004777. In some embodiments, reference to the term DOT1L inhibitor includes any such DOT1L inhibitor disclosed in any one of the following patent applications: WO 2016090271, WO 2014100662, and CN 108997480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. iix) UBA1 In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more ubiquitin-activating enzyme inhibitors (e.g., a UBA1 inhibitor). A UBA1 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. UBA1, also known as ubiquitin-activating enzyme 1, is a key enzyme involved in the ubiquitination process, a fundamental cellular mechanism for protein degradation and regulation. Ubiquitination involves the covalent attachment of ubiquitin molecules to target proteins, marking them for degradation by the proteasome or modulating their activity, localization, or interactions within the cell. Several inhibitors have been developed to modulate UBA1 activity, with the aim of disrupting ubiquitination-mediated processes in diseased cells. These inhibitors include but are not limited to PATENT ATTORNEY DOCKET NO.: 51432-067WO2 adenosine-based inhibitors which typically compete with ATP for binding to the active site of UBA1, thereby preventing the activation of ubiquitin (e.g., PYR-41 and MLN7243); covalent inhibitors which form irreversible bonds with specific amino acid residues in the active site of UBA1, leading to inhibition of its activity (e.g., TAK-243 (formerly known as MLN4924)); allosteric inhibitors which bind to sites on UBA1 distinct from the active site, inducing conformational changes that inhibit its catalytic activity (e.g., compound 2i); and fragment-based inhibitors which are designed based on smaller molecular fragments that bind to UBA1. In some embodiments, a UBA1 inhibitor is one or more of PYR-41, MLN7243, and TAK-243. In some embodiments, reference to the term UBA1 inhibitor includes any such UBA1 inhibitor disclosed in any one of the following patent applications: WO 2016069393 A1, WO 2016069392 A1, and JP 2013237627 A2, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. l) Ribonucleotide reductase inhibitors Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more ribonucleotide reductase inhibitors (RNRi). RNR inhibitors are a class of compounds that inhibit the enzyme ribonucleotide reductase, which is essential for DNA synthesis and repair. RNR catalyzes the conversion of ribonucleotides (RNA building blocks) into deoxyribonucleotides (DNA building blocks), providing the necessary precursors for DNA replication and repair in proliferating cells. By inhibiting RNR, these compounds effectively limit the production of deoxyribonucleotides, thereby preventing DNA synthesis and halting the proliferation of rapidly dividing cells, such as cancer cells. RNR is composed of two subunits: the R1 large subunit (containing the catalytic site) and the R2 small subunit (containing a di-iron center critical for enzymatic activity). RRIs typically act by binding to either the active site on the R1 subunit or the iron-oxygen complex in the R2 subunit, leading to the inhibition of the enzyme's activity. In some embodiments, a RNR inhibitor is a nucleoside analog inhibitor, an iron chelator, or an allosteric inhibitor. In some embodiments, a RNR inhibitor useful according to the present disclosure include but are not limited to one or more of hydroxyurea, triapine, didox, GTI-2040, CPI-613 (devimistat), and clofarabine. In some embodiments, reference to the term RNR inhibitor includes any such RNR inhibitor disclosed in any one of the following patent applications: WO 2025049814, WO 2022059691, WO 2022059692, WO 2021034776, WO 2019106579, WO 2014205179, WO 2013105088, WO 199312782, US 5,071,835, US 5,405,850, US 4,814,432, and WO 199518815 each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. m) Additional Therapeutic Agents Useful for Combination Therapy In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Farnesyl transferase inhibitors. A farnesyl transferase inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. Farnesyl transferase inhibitors (FTIs) are a class of drugs that target the farnesyl transferase enzyme, which plays a role in a process called protein prenylation. Protein prenylation is an important step in the process of activating certain proteins involved in signal transduction, cell growth, and differentiation. In PATENT ATTORNEY DOCKET NO.: 51432-067WO2 some embodiments, a farnesyl transferase inhibitor is one or more of tipifarnib, lonafarnib, and rilapladib. In some embodiments, reference to the term farnesyl transferase inhibitor includes any such farnesyl transferase inhibitor disclosed in any one of the following patent applications: WO 2010057028, WO 2007042465, WO 200136395, WO 200064891, WO 200042849, WO 199938862, WO 199928315, WO 199829390, WO 199426723, CN 107312000, CN 107365310, KR 100375421, KR 100388790, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, compositions and methods described herein may include a RAS(ON) multi-selective inhibitor of the present disclosure in combination with one or more casein kinase inhibitors. In some embodiments, a casein inhibitor is, SR-3029, a potent and ATP competitive CK1δ and CK1ε inhibitor. In some embodiments, compositions and methods described herein may include one or more FLT3 inhibitors in combination with a RAS(ON) inhibitor of the present disclosure disclosed herein. FLT3 (Fms-like tyrosine kinase 3), also known as CD135, is a receptor tyrosine kinase (RTK) that plays a crucial role in regulating hematopoiesis, the process by which blood cells are formed. It is primarily expressed on hematopoietic stem cells (HSCs) and progenitor cells in the bone marrow, where it controls cell proliferation, survival, and differentiation. In some embodiments, a FLT3 inhibitor includes, but are not limited to, midostaurin, gilteritinib, sorafenib, quizartinib, crenolanib, ponatinib and quizartinib. In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more one or more TGFβ pathway inhibitors. In some embodiments, compositions and methods described herein may include one or more TGFβ inhibitors. A TGFβ inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. TGFβ (transforming growth factor beta) is a multifunctional cytokine involved in various cellular processes, including cell growth, differentiation, apoptosis, and immune response. Dysregulation of the TGFβ signaling pathway has been implicated in various diseases, including cancer, fibrosis, and autoimmune disorders. In some embodiments, a TGFβ inhibitor is one or more of galunisertib (LY2157299), and vactosertib (TEW-7197). In some embodiments, a TGFβ inhibitor is one or more of Galunisertib, LY2157299, Fresolimumab, Lerdelimumab, Trabedersen, curcumin, resveratrol and small interfering RNA (siRNA) to silence TGFβ receptor expression. In some embodiments, reference to the term TGFβ inhibitor includes any such TGFβ inhibitor disclosed in any one of the following patent applications: WO 2023043473, WO 2020104648, WO 2020128850, WO 2016140884, WO 2007018818, WO 2004024159, WO 200226935, WO 2002062753, WO 2002062776, and JP 2012087076, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more HSP90 inhibitors. A HSP90 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. HSP90, also known as heat shock protein 90, is a molecular chaperone that plays a critical role in regulating the folding, stability, and activity PATENT ATTORNEY DOCKET NO.: 51432-067WO2 of a large number of client proteins involved in various cellular processes, including cell cycle progression, signal transduction, and apoptosis. In some embodiments, a HSP90 inhibitor is one or more of Geldanamycin and its derivatives (e.g., 17-AAG, 17-DMAG), KOS 953, Radicicol and its derivatives (e.g., PU-H71), SNX-2112, Ganetespib, AT13387, Onalespib, Luminespib, and KW-2478. In some embodiments, reference to the term HSP90 inhibitor includes any such HSP90 inhibitor disclosed in any one of the following patent applications: WO 2021137665, WO 2018200534, WO 2017151425, WO 2015200514, WO 2013053833, WO 2013009657, WO 2013119985, WO 2012138894, WO 2011044394, WO 2009097578, WO 2008115719, CN 105237533, and CN 104030904, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Glutathione peroxidase 4 (GPX4) inhibitors. A GPX4 inhibitor may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. GPX4 is an antioxidant enzyme that plays a critical role in protecting cells against oxidative stress- induced cell death. GPX4 catalyzes the reduction of lipid hydroperoxides to their corresponding alcohols and acts as a regulator of ferroptosis, a form of regulated cell death driven by lipid peroxidation. In some embodiments, a GPX4 inhibitor is one or more of RSL3, ML162, DPI7, FINO2, MCB-613, CBS9106, ML210, ODSH, and TLN232. In some embodiments, reference to the term GPX4 inhibitor includes any such GPX4 inhibitor disclosed in any one of the following patent applications: WO 2021132592, US 2021244715, and KR 20220115536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more NRF2 inhibitors. A NRF2 inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. NRF2 is a transcription factor that regulates the expression of genes involved in the cellular antioxidant response, detoxification, and other cytoprotective pathways. It plays a critical role in cellular defense mechanisms against oxidative stress and other forms of cellular damage. In some embodiments, a NRF2 inhibitor is one or more of ML385, Brusatol, CDDO-Im, RTA-408, and trigonelline. In some embodiments, reference to the term NRF2 inhibitor includes any such NRF2 inhibitor disclosed in any one of the following patent applications: WO 2023051088, WO 2021202720, KR 2022013610, and CN 107519168, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more TEA domain (TEAD) inhibitors. A TEAD inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. TEAD is a family of transcription factors that play a key role in regulating gene expression during embryonic development and PATENT ATTORNEY DOCKET NO.: 51432-067WO2 tissue homeostasis. The four members of the TEAD family (TEAD1-4) are transcriptional co-activators that bind to DNA through their conserved TEA domain and interact with other transcription factors to activate the expression of target genes. In some embodiments, a TEAD inhibitor is one or more of VT3989, VT-107, a pan-TEAD, VT-104, Verteporfin, CA3, IAG933, K-975, IK-595, and Statins (see, e.g., Chapeau, Emilie and Schmelzle, Tobias (2023) IAG933, an oral selective YAP1-TAZ / pan-TEAD protein- protein interaction inhibitor (PPIi) with pre-clinical activity in monotherapy and combinations with MAPK inhibitors. Nature cancer). In some embodiments, reference to the term TEAD inhibitor includes any such TEAD inhibitor disclosed in any one of the following patent applications: WO 2023280254, WO 2023031781, WO 2022258040, WO 2020070181 WO 2018185266, and WO 2017064277, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more NOTCH / Gamma secretase inhibitors. A NOTCH / Gamma secretase inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. In some embodiments, a NOTCH / Gamma secretase inhibitor is nirogacestat. In some embodiments, reference to the term NOTCH / Gamma secretase inhibitor includes any such NOTCH / Gamma secretase inhibitor disclosed in any one of the following patent applications: WO 2020208572, WO 2017200969, WO 2014047390, WO 2014047372, WO 2011041336, WO 2010090954, WO 2009008980, WO 2009087130, WO 2007110335, CN 103664904, CN 105560244, and KR 20200077480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Hedgehog inhibitors. A hedgehog inhibitor may be administered or formulated in combination with A RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. The hedgehog (Hh) family of proteins are secreted signaling molecules that play a crucial role in embryonic development and tissue homeostasis in adults. The Hh signaling pathway is involved in regulating cell growth, differentiation, and survival. In some embodiments, a hedgehog inhibitor is one or more of Vismodegib (ERIVEDGE®), Sonidegib (ODOMZO®), and Glasdegib (DAURISMOTM). In some embodiments, reference to the term hedgehog inhibitor includes any such hedgehog inhibitor disclosed in any one of the following patent applications: WO 2011063309, and CN 107163028, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. Compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more NFkB pathway inhibitors. An NFkB inhibitor may be administered or formulated in combination with a RAS(ON) multi-selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. NF-kappa B (NFκB) is a family of transcription factors involved in regulating various cellular processes, including inflammation, immunity, cell survival, and proliferation. Non-limiting examples of NFkB inhibitors include Bortezomib PATENT ATTORNEY DOCKET NO.: 51432-067WO2 (VELCADE®), Curcumin, Parthenolide, IKK inhibitors (e.g., IKK-16, BAY 11-7082), Resveratrol, Andrographolide and Proteasome inhibitors (e.g., MG132, lactacystin). In some embodiments, the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence or severity of side effects of treatment. For example, in some embodiments, a RAS(ON) multi-selective inhibitor of the present disclosure can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof. In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies includes a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T cell adoptive transfer (ACT) therapy. In some embodiments, a RAS(ON) multi-selective inhibitor of the present disclosure may be used as an adjuvant therapy after surgery. In some embodiments, a RAS(ON) inhibitor of the present disclosure may be used as a neo-adjuvant therapy prior to surgery. Radiation therapy may be used for inhibiting abnormal cell growth or treating a hyperproliferative disorder, such as cancer, in a subject (e.g., mammal (e.g., human)). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered through one of several methods, or a combination of methods, including, without limitation, external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachy therapy. The term "brachy therapy," as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, or Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres. In some embodiments, a RAS(ON) inhibitor of the present disclosure can render abnormal cells more sensitive to treatment with radiation for purposes of killing or inhibiting the growth of such cells. Accordingly, this disclosure further relates to a method for sensitizing abnormal cells in a mammal to PATENT ATTORNEY DOCKET NO.: 51432-067WO2 treatment with radiation which comprises administering to the mammal an amount of a RAS(ON) multi- selective inhibitor of the present disclosure, which amount is effective to sensitize abnormal cells to treatment with radiation. The amount of the compound in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein. In some embodiments, a RAS(ON) multi-selective inhibitor of the present disclosure may be used as an adjuvant therapy after radiation therapy or as a neo-adjuvant therapy prior to radiation therapy. In some embodiments, the non-drug treatment is a T cell adoptive transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell may be modified to express a chimeric antigen receptor (CAR). CAR modified T (CAR-T) cells can be generated by any method known in the art. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present disclosure, any number of T cell lines available in the art may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041. In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the present disclosure in combination with one or more Claudin-18 targeting agents. A Claudin-18 targeting agent may be administered or formulated in combination with a RAS(ON) multi- selective inhibitor of the present disclosure and / or any additional therapeutic agent described herein. Claudin-18 (e.g., claudin 18.2; CLDN18.2) has become a promising target for the treatment of patients with digestive malignancies, such as gastric cancer (GC), gastroesophageal junction (GEJ) cancer, esophageal cancer, and pancreatic cancer, because of its limited expression in healthy tissues and abnormal overexpression in a range of malignancies. Multiple clinical trials of CLDN18.2-targeted therapies, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies, are ongoing, with some showing promising early results. Malignant transformation of gastric epithelial tissue leads to disruption of cell polarity and then to exposure of CLDN18.2 epitopes on the cell surface. Although targeted monoclonal antibodies are largely unable to access CLDN18.2 located in tight-junction supramolecular complexes in normal tissue, the perturbations in cell polarity that expose CLDN18.2 epitopes may theoretically enable CLDN18.2 targeted agents to bind to CLDN18.2 in malignant tissues with minimal off-target effects, making CLDN18.2 an attractive target for therapy. In some embodiments, a Claudin-18 targeting agent is one or more of Zolbetuximab, ASKB589, Osemitamab (TST001), PT886 (a bispecific antibody that targets CLDN18.2 and CD47), TJ-CD4B, CMG901 (an ADC that is composed of an antiCLDN18.2 monoclonal antibody joined to a cytotoxic payload, monomethyl auristatin E), and CT041 (autologous T cells genetically engineered to express a CLDN18.2-targeted CAR). In some embodiments, reference to the term Claudin- PATENT ATTORNEY DOCKET NO.: 51432-067WO2 18 targeting agent includes any such Claudin-18 targeting agent disclosed in any one of the following patent applications: WO 2024081544, WO 2024131683, WO 2024137619, WO 2024140670, WO 2024136594, WO 2023034922, WO 2023046202, WO 2022203090, WO 2022133169, WO 2022100613, WO 2022256449, WO 2022136642, WO 2021155380, WO 2021129765, WO 2021011885, WO 2021058000, WO 2021218874, WO 2021027850, WO 2020156554, WO 2020025792, WO 2020114480, WO 2020211792, WO 2020239005, WO 2019219089, WO 2018157147, WO 2018108106, WO 2016166122, WO 2014146778, CN 118290582, CN118203658, and CN 118286201, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein which are specifically incorporated herein by reference. In some embodiments, a therapeutic agent for combination therapy may be a steroid. Accordingly, in some embodiments, the one or more additional therapies includes a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof. Further examples of therapeutic agents that may be used in combination therapy with a RAS(ON) inhibitor of the present disclosure include compounds described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patent Applications WO 200137820, WO 200132651, WO 200268406, WO 200266470, WO 200255501, WO 200405279, WO 200407481, WO 200407458, WO 200409784, WO 200259110, WO 199945009, WO 2000 / 59509, WO 199961422, WO 200012089, and WO 200002871. An additional therapeutic agent may be a biologic (e.g., cytokine (e.g., interferon or an interleukin such as IL-2)) used in treatment of cancer or symptoms associated therewith. In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer. Also included are antibody-drug conjugates. An additional therapeutic agent may be an immune modulatory agent. For example, an additional therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an PATENT ATTORNEY DOCKET NO.: 51432-067WO2 agent, such as an antibody, which interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, A2bR, A2aR / A2bR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as, e.g., avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene) or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW- 6002. Non-limiting examples of immune modulatory agent includes targets identified in Table 2. Table 2: Exemplary Immune Modulatory Targets PATENT ATTORNEY DOCKET NO.: 51432-067WO2 CTLA4, cytotoxic T-lymphocyte-associated antigen 4; LAG3, lymphocyte activation gene 3; PD-1,programmed cell death protein 1; PD-L1, PD-1 ligand; TIM3, T cell membrane protein 3; VISTA, V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation; KIR, killer lgG-like receptor, APC (Antigen Presenting Cells); TREM2 (Triggering receptor expressed on myeloid cells 2); TGF-b (Transforming growth factor beta) In some embodiments, compositions and methods described herein may include a RAS(ON) inhibitor of the disclosure in combination with one or more immune checkpoint inhibitor (ICI). An immune checkpoint inhibitor may be administered or formulated in combination with a compound as described herein. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system, which, under normal physiological conditions are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues to minimize collateral tissue damage in response to pathogenic infection. However, the expression of immune checkpoint proteins is often dysregulated by tumors as an important immune resistance and escape mechanism. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Thus, inhibition of these pathways has been used to activate therapeutic anti-tumor immunity. For example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies were the first of this class of immunotherapeutic to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with inhibitors of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD-1), indicate broad and diverse opportunities to enhance anti-tumor immunity with the potential to produce durable clinical responses. T cell activation through blockade of immune checkpoints has been a major focus of efforts to therapeutically manipulate endogenous anti-tumor immunity, owing to the capacity of T cells for the selective recognition of peptides derived from proteins in all cellular compartments; their capacity to directly recognize and kill antigen-expressing cells (by CD8+ effector T cells; also known as cytotoxic T lymphocytes (CTLs)); and their ability to orchestrate diverse immune responses (by CD4+ helper T cells), which integrate adaptive and innate effector mechanisms. Thus, agonists of co-stimulatory receptors or PATENT ATTORNEY DOCKET NO.: 51432-067WO2 antagonists of inhibitory signals, both of which result in the amplification of antigen-specific T cell responses, are currently agents of interest in clinical testing. ICIs approved or in development include, but are not limited to, YERVOY® (ipilimumab), OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab), tremelimumab, galiximab, MDX-1106, BMS- 936558, MEDI4736, MPDL3280A, MEDI6469, BMS-986016, BMS-663513, PF-05082566, IPH2101, KW- 0761, CDX-1127, CP-870, CP-893, GSK2831781, MSB0010718C, MK3475, CT-011, AMP-224, MDX- 1105, IMP321, and MGA271, as well as numerous other antibodies or fusion proteins directed to the immune checkpoint proteins noted in Table 1. Common immune checkpoint proteins that may be targeted by ICIs include, but are not limited to B7.1, B7-H3, LAG3, CD137, KIR, CCR4, CD27, OX40, GITR, CD40, CTLA4, PD-1, and PD-L1. In some embodiments, the immune checkpoint inhibitor is an inhibitor of a target selected from the group comprising or consisting of programmed cell death protein-1, ligand of PD- 1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), B7 homolog 3 protein (B7-H3), B- and T- lymphocyte attenuator (BTLA), Sialic acid binding Ig-like lectin 15 (Siglec-15), cytokine-inducible SH2- containing protein (CISH), and combination thereof. In some embodiments, the ICI therapy is selected from one or more of anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-LAG3, anti-B7.1, anti-B7H3, anti-B7H4, anti-TIM3, anti-VISTA, anti-CD137, anti-OX40, anti-CD40, anti-CD27, anti-CCR4, anti-GITR, anti-NKG2D, and anti-KIR. In some embodiments, the ICI therapy is an antibody (e.g., a monoclonal antibody selective for any of the targets in Table 1). In some embodiments the ICI is an anti-PD-1 antibody. The antibody may be, e.g., humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti- CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN- 15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as, e.g., avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (also known as tislelizumab; BeiGene & Celgene) or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002. PATENT ATTORNEY DOCKET NO.: 51432-067WO2 In some embodiments, the immune checkpoint inhibitor is an inhibitor of programmed cell death protein- 1 (PD-1) or an inhibitor of the ligand of PD-1 (PDL-1). Programmed cell death protein-1 is herein interchangeably referred to as PD-1, PD1, PDCD1, PDCD-1, SLEB2, SLE1 and CD279. In humans, PD-1 typically has the sequence as disclosed in UniProtKB Ref. Q15116, incorporated herein by reference. Programmed death-ligand 1 is herein interchangeably referred to as PDL-1, PD-Ll, PDL1, PDCD1L1, PDCD1LG1, CD274, B7-H1, B7-H, B7H1. In humans, PD-L1 typically has the sequence as disclosed in UniProtKB Ref. Q9NZQ7, incorporated herein by reference. In some embodiments, the anti-PD1 antibody is cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, sasanlimab, retifanlimab, tebotelimab, ABBV-181, AK104, AK105, BCD-100, BI-754091, CBT-501, CC-90006, GLS- 010, HLX10, IBI-308, JNJ-3283, JS001, LZM009, MEDI0680 (AMP-514), REGN-2810, SHR-1210, Sym021, TSR-042, or XmAb20717. In some embodiments, the PD-1 inhibitor is a bispecific antibody specific for PD-1 and VEGF. In some embodiments, the bispecific antibody is ivonescimab (SMT112). In some embodiments, the bispecific antibody is BNT327. In some embodiments, the bispecific antibody is SYN-2510. In some embodiments, the anti-PDL1 antibody is atezolizumab, avelumab, durvalumab, envafolimab, FS118, BCD-135, BGB-A333, BGBA-317, CBT-502, CK-301, CS1001, FAZ053, MDX-1105, MSB2311, SHR-1316, M7824, LY3415244, CA-170, or CX-07Z. An additional therapeutic agent may be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A or OMP-313M32 (etigilimab). In some embodiments, the combination therapy includes a RAS(ON) inhibitor of the disclosure and an anti-CCR8 antibody. In an embodiment, the anti-CCR8 antibody is an afucosylated antibody. In an embodiment, the anti-CCR8 antibody is a depleting antibody. In an embodiment, the anti-CCR8 antibody has ADCC activity. In an embodiment, the anti-CCR8 antibody is a neutralizing antibody. In an embodiment, the anti-CCR8 antibody is not a neutralizing antibody. In an embodiment, the anti-CCR8 antibody is BMS-986340. In an embodiment, the anti-CCR8 antibody is GS-1811. In an embodiment, the anti-CCR8 antibody is ABBV-514. In an embodiment, the anti-CCR8 antibody is LM-108. In an embodiment, the anti-CCR8 antibody is S-531011. In an embodiment, the anti-CCR8 antibody is BAY3375968. In an embodiment, the anti-CCR8 antibody is SRFl 14. In an embodiment, the anti-CCR8 antibody is CM369. In an embodiment, the anti-CCR8 antibody is ZL-1218. In an embodiment, the anti- CCR8 antibody is IPG0521.In an embodiment, the anti-CCR8 antibody is an anti-CCR8 antibody disclosed in WO 2025076288, WO 2022256563, WO2022004760, WO2022136649, WO 2021142002, WO 2021194942, WO 2021260206, WO 2021260208, WO 2021260210, WO 2021260209, WO 2021152186, WO 2020138489, and WO 2018181425 which are incorporated herein by reference including the structures disclosed therein. In some embodiments, the combination therapy includes a RAS(ON) inhibitor of the disclosure and a cancer vaccine composition. In some embodiments, the cancer vaccine composition is ELI-0022P, PATENT ATTORNEY DOCKET NO.: 51432-067WO2 ELI-0027P, HB-700, mRNA-4157, mRNA-5671, BNT111, GVAX Pancreas, IMA901, DCVax, SOT101, Sipuleucel-T, PROSTVAC-VF or TG01. In some embodiments, the combination therapy includes a RAS(ON) inhibitor of the disclosure and an additional therapy or therapeutic agent selected from group consisting of RAS pathway targeted therapeutic agents, kinase-targeted therapeutics, mTORC1 inhibitors or degraders, YAP inhibitors or degraders, proteasome inhibitors or degraders, HSP90 inhibitors or degraders, farnesyl transferase inhibitors or degraders, PTEN inhibitors or degraders, signal transduction pathway inhibitors or degraders, checkpoint inhibitors, modulators of the apoptosis pathway, chemotherapeutics, angiogenesis- targeted therapies, immune-targeted agents, radiotherapy, and combinations thereof. An additional therapeutic agent may be an agent that treats cancer or symptoms associated therewith (e.g., a cytotoxic agent, non-peptide small molecules, or other compound useful in the treatment of cancer or symptoms associated therewith, collectively, an “anti-cancer agent”). Anti-cancer agents can be, e.g., chemotherapeutics or targeted therapy agents. Anti-cancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and r...

Claims

PATENT ATTORNEY DOCKET NO.: 51432-067WO2 Claims 1. A method of treating a RAS protein-related disease in a subject in need thereof, the method comprising administering to the subject a RAS(ON) inhibitor and a CypA-binding compound.

2. The method of claim 1, wherein the CypA-binding compound is administered locally.

3. The method of claim 1 or 2, wherein the CypA-binding compound is administered in an amount sufficient to treat or prevent a RAS(ON) inhibitor treatment-related adverse event resulting from administration of the RAS(ON) inhibitor.

4. The method of any one of claims 1 to 3, wherein the CypA-binding compound is administered prior to administration of the RAS(ON) inhibitor.

5. The method of any one of claims 1 to 3, wherein the CypA-binding compound is administered prior to and during administration of the RAS(ON) inhibitor.

6. The method of any one of claims 1 to 3, wherein the CypA-binding compound is administered after administration of the RAS(ON) inhibitor when a RAS(ON) inhibitor treatment-related adverse event occurs.

7. The method of any one of claims 1 to 6, wherein the CypA-binding compound is administered to normal tissue.

8. The method of any one of claims 1 to 7, wherein the CypA-binding compound is administered to tissue at risk of a RAS(ON) inhibitor treatment-related adverse event.

9. The method of any one of claims 1 to 8, wherein the CypA-binding compound is administered to the oral cavity, skin, or gastrointestinal tract.

10. The method of any one of claims 1 to 9, wherein the CypA-binding compound is one or more of cyclosporin A, N-methyl-4-isoleucine cyclosporin, alisporivir, SCY-635, sanglifehrin A, Compound 3, analogs, derivatives, or pharmaceutically acceptable salts thereof.

11. The method of any one of claims 1 to 10, wherein the CypA-binding compound is cyclosporin, sanglifehrin A, NIM811, alisporivir, SCY-635, or Compound 3.

12. The method of any one of claims 1 to 11, wherein the RAS(ON) inhibitor is a RAS(ON) multi- selective inhibitor, a RAS(ON) mutant-selective inhibitor, or a combination thereof.PATENT ATTORNEY DOCKET NO.: 51432-067WO2 13. The method of claim 12, wherein the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12C- selective inhibitor, a RAS(ON) G12D-selective inhibitor, a RAS(ON) G13C-selective inhibitor, a RAS(ON) Q61H-selective inhibitor, a RAS(ON) G12V-selective inhibitor, a RAS(ON) G13D- selective inhibitor, or a RAS(ON) G12R-selective inhibitor.

14. The method of any one of claims 1 to 13, wherein the RAS(ON) multi-selective inhibitor is RMC- 6236 (daraxonrasib) RMC-7977, Compound 6A of WO 2024067857, or ERAS-0015.

15. The method of any one of claims 1 to 14, wherein the subject has a mutation of RAS.

16. The method of claim 15, wherein the mutation of RAS is a KRAS mutation.

17. The method of claim 15 or 16, wherein the mutation is at G12X, wherein X is A, C, D, V, S, or R amino acid residue.

18. The method of claim 15 or 16, wherein the mutation is at G13X, wherein X is A, C, D, V, S, or R amino acid residue.

19. The method of claim 15 or 16, wherein the mutation is at Q61X, wherein X is A, C, D, V, S, R, H, K, or L amino acid residue.

20. The method of any one of claims 1 to 19, wherein the RAS protein-related disease is cancer.

21. The method of claim 20, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

22. The method of claim 21, wherein the lung cancer is non-small cell lung cancer.

23. The method of claim 21, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

24. The method of any one of claims 1 to 23, further comprising administering an additional therapeutic agent.

25. The method of claim 24, wherein the additional therapeutic agent is a second RAS inhibitor, a SOS1 inhibitor, a SHP inhibitor, a MEK inhibitor, a RAF inhibitor, an ERK inhibitor, a MAPK inhibitor, a PKA inhibitor, a FAK inhibitor, a ROCK inhibitor, a MSK1 inhibitor, a RSK inhibitor, an ALK inhibitor, an EGFR inhibitor, a HER2 inhibitor, a MET inhibitor, an AXL inhibitor, an IGFR inhibitor, a RET inhibitor, a ROS1 inhibitor, a PDGFR inhibitor, an FGF inhibitor, a VEGF inhibitor, a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, an MNK inhibitor, an eIF4 inhibitor, a Wee1PATENT ATTORNEY DOCKET NO.: 51432-067WO2 inhibitor, a CHK inhibitor, an ATM inhibitor, an ATR inhibitor, a PARP inhibitor, a DNA-PK inhibitor, a CDK inhibitor, an Aurora kinase inhibitor, a PLK inhibitor, a DYRK1 inhibitor, an ULK1 inhibitor, a VPS inhibitor, a micropinocytosis inhibitor, a beta-catenin inhibitor, a PORCN inhibitor, a GSK3 inhibitor, a CLK inhibitor, a JAK inhibitor, a STAT inhibitor, a HDAC inhibitor, a BET inhibitor, an EZH2 inhibitor, a Co-REST inhibitor, an EP300 inhibitor, an LSD1 inhibitor, a PRMT5 inhibitor, a MAT2A inhibitor, a DOT1L inhibitor, a UBA1 inhibitor, a ribonucleotide reductase inhibitor, a farnesyl transferase inhibitor, a casein kinase inhibitor, a FLT3 inhibitor, a TGF-beta pathway inhibitor, a HSP90 inhibitor, a Glutathione Peroxidase 4 (GPX4) inhibitor, a NRF2 inhibitor, a TEA domain (TEAD) inhibitor, a NOTCH / Gamma secretase inhibitor, a Hedgehog inhibitor, a NFkappa-beta pathway inhibitor, surgery, radiation, chemotherapy, T cell adoptive transfer therapy, a Claudin-18 targeting agent, anti-CTLA, anti-PD-1, anti-PDL1, a B7-H3 inhibitor or antagonist, a B7-H4 inhibitor or antagonist, a BTLA inhibitor or antagonist, a HVEM inhibitor or antagonist, a TIM3 inhibitor or antagonist, a GAL9 inhibitor or antagonist, a LAG3 inhibitor or antagonist, a VISTA inhibitor or antagonist, a KIR inhibitor or antagonist, a 2B4 inhibitor or antagonist, a CD160 inhibitor or antagonist, a CGEN-15049 inhibitor or antagonist, an A2aR inhibitor or antagonist, an A2bR inhibitor or antagonist, an A2aR / A2bR inhibitor or antagonist, B-7 family ligands, and / or a RAS targeting cancer vaccine.

26. The method of claim 25, wherein the first RAS(ON) multi-selective inhibitor and the second RAS inhibitor are not identical.

27. The method of claim 26, wherein the second RAS inhibitor is a RAS(OFF) inhibitor.

28. The method of claim 27, wherein the second RAS inhibitor is a pan-KRAS inhibitor.

29. The method of any one of claims 1 to 28, wherein the RAS(ON) inhibitor potency in normal tissues is decreased upon administration of the CypA-binding protein while maintaining antitumor activity of the RAS(ON) inhibitor in tumor tissue.

30. The method of any one of claims 1 to 28, wherein the subject does not exhibit any dose limiting toxicity associated with the RAS(ON) inhibitor.

31. The method of any one of claims 1 to 28, wherein the frequency or severity of treatment-related adverse events are reduced compared to the frequency or severity of treatment-related events without administration of a CypA-binding compound.

32. The method of claim 31, wherein the treatment-related adverse event is an on-target RAS- pathway mediated toxicity.

33. The method of any one of claims 3 to 32, wherein the treatment-related adverse event is rash.PATENT ATTORNEY DOCKET NO.: 51432-067WO2 34. The method of any one of claims 3 to 32, wherein the treatment-related adverse event is mucositis.

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