CDK2 inhibitor for the treatment of KRAS mutant cancer

Abstract

Combinations, compositions and uses of a cyclin dependent kinase 2 (CDK2) inhibitor INX-315, or a pharmaceutically acceptable salt thereof described herein, in combination with a CDK4 / 6 inhibitor for the treatment of disorders characterized by mutation of Kirsten rat sarcoma (KRAS), including but not limited to the treatment of tumors and cancers. In addition, the invention includes a method to delay acquired resistance to a RAS inhibitors in a KRAS mutant cancer, comprising administering the CDK2 inhibitor INX-315 optionally in combination or alternation with a KRAS inhibitor.

Description

[0001] CDK2 INHIBITOR FOR THE TREATMENT OF

[0002] KRAS MUTANT CANCER

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application 63 / 696,230 filed on September 18, 2024. The entirety of this application is hereby incorporated by reference for all purposes.

[0005] FIELD OF THE INVENTION

[0006] The invention provides improved combinations, compositions and methods for the use of the selective CDK2 inhibitor INX-315, to treat a patient with a KRAS mutant cancer, typically a human, in need thereof, as described in more detail below.

[0007] BACKGROUND

[0008] Cancer remains among the most lethal threats to human health. In the United States alone, in 2024, there were over 2 million new cancer diagnoses, and over 600,000 deaths. It is the second leading cause of death in the U.S.

[0009] The Kirsten rat sarcoma protein (KRAS) is part of the RAS / MAPK pathway. KRAS is involved with normal cell growth division and proliferation. KRAS mutations are the most common oncogene found in human cancers and are associated with poor outcomes. Hood, et al., “The Frequency of Ras Mutations in Cancer”, Cancer Research (2020) 80(14) 2969-2974.

[0010] The therapeutic development of effective therapies in KRAS mutant cancer has been a long and challenging pursuit for researchers, even earning KRAS the nickname, “the undruggable gene” (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15: 152(2022)). Several KRAS targeting agents have been developed and approved by the United States Food and Drug Administration (FDA), although for various specific subsets of KRAS mutant patients (Huang, L. et al. KRAS mutation: from undruggable to druggable in cancer. Sig Transduct Target Ther. 6(l):386(2021 Nov 15)). For example, the KRAS G12C irreversible inhibitors Sotorasib (Lumakras®) and adagrasib (Krazati®) are indicated for locally advanced or metastatic non-small cell lung cancer (NSCLC). These inhibitors covalently bind the mutant Cys-12 residue which locks the protein into an inactive state to prevent downstream signaling. Because these inhibitors target the mutant KRAS G12C form, the wild-type KRAS protein is expected to be unaffected (Lumakras® Package Insert (2022 Dec); Krazati® Package Insert (2021 May)). However, these drugs are only effective on KRAS G12C mutated cancer.

[0011] Given the outsized role of mutated KRAS in human cancer, there remains an unmet medical need for new compositions and therapeutic regimens to treat abnormal cellular proliferation such as cancer that is driven by a mutant form of KRAS in a host such as a human in need thereof.

[0012] Therefore, it is an object of the present invention to provide new compositions and methods for treating cancer that has a mutant form of KRAS in a host such as a human.

[0013] SUMMARY

[0014] The present invention provides advantageous combinations, compositions and methods for treating a cancer with a KRAS mutation based on the surprising discovery that the CDK2 inhibitor INX-315, which has the chemical structure: or its pharmaceutically acceptable salt may provide at least one of the following unexpected treatment benefits: i) INX-315 can be administered to treat a host, for example a human, to treat a mutant KRAS cancer when used in combination with a CDK4 / 6 inhibitor; ii) INX-315, when administered to treat a host, for example, a human, with a mutant KRAS cancer, delays the development of resistance of the mutant KRAS cancer to a RAS inhibitor; iii) INX-315, when administered to treat a host, for example a human, with a mutant KRAS cancer that has decreased sensitivity to a RAS inhibitor, resensitizes the cancer to a RAS inhibitor; iv) INX-315, can be effectively administered to treat a host such as a human with a mutant KRAS cancer that has a p53 loss of function; which also allows p53 to be used as a biomarker for efficacy; and / or v) INX-315 can be advantageously administered to a host, such as a human, in need thereof in combination or alternation with a CDK1 inhibitor for the treatment of a cyclin El (CCNE1) amplified cancer.

[0015] In certain embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12V, KRAS G13D, and KRAS Q61H.

[0016] INX-315 has been disclosed in WO 2021 / 236650, published November 25, 2021, and U.S. Patent No. 11,643,416 as well as WO 2023 / 249974, published December 28, 2023. See also Dietrich, et al., “INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors”, Cancer Discovery March 2024.

[0017] The specific combination of INX-315 with a CDK4 / 6 inhibitor as described herein provides significant advantageous or synergistic inhibition of KRAS mutant cancer growth and viability, which increases therapeutic effectiveness. Separately, improved compositions and methods for delaying acquired resistance to RAS inhibitors were unexpectedly discovered as described herein, comprising administering the CDK2 inhibitor INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with a RAS inhibitor to a patient in need thereof. By incorporating the CDK2 inhibitor INX-315 into combination therapies as described herein, the select combinations provide efficacious anti-cancer treatments of KRAS mutant cancers and are capable of long-term administration.

[0018] In a first aspect of this invention, advantageous combinations, compositions and methods for treating a patient having a KRAS mutant cancer are provided, comprising administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor, or a pharmaceutically acceptable salt thereof. Unexpectedly, the CDK2 inhibitor compound significantly, and perhaps synergistically, improved the response of CDK4 / 6 inhibitor in a variety of KRAS mutant cancers (see, e.g., Examples 1-2, FIGs. 1, 2A-2B, 3A-3B, 4). It was also surprisingly discovered herein that INX-315 improves the response of a CDK4 / 6 inhibitor (e.g., palbociclib) in a dose-dependent manner in different models of KRAS mutant cancer (see, e.g., Example 3, FIG. 5A-5C).

[0019] It was also unexpectedly discovered that the CDK2 inhibitor compound INX-315 can sensitize KRAS mutant cancers to CDK4 / 6 inhibitor treatment. For example, and as described in Example 4 herein, the addition of the CDK2 inhibitor compound INX-315 provoked the sensitization of KRAS mutant cell lines to CDK4 / 6 inhibitor therapy where there previously was no substantial response (see, e.g., FIG. 6A). Surprisingly, the improvement in CDK4 / 6 inhibitor therapy response mediated by INX-315 is not dictated by cancer cell origin (see, e.g., FIG. 6C). Moreover, it was discovered that the combination of INX-315 and a CDK4 / 6 inhibitor (palbociclib) substantially reduces cell colony outgrowth greater than other treatments in different KRAS mutant cells, with effects comparable to that of INX-315 in combination with a RAS inhibitor and exceeding the effect of RAS inhibitor alone (see, e.g., Example 6, FIG. 8A-8C). In some nonlimiting examples, the combination of INX-315 and a CDK4 / 6 inhibitor completely eliminated pancreatic cancer model MIA PaCa2 cell colonies which carry a mutation encoding a KRAS G12C substitution (see, e.g., Example 6, FIG. 8C). This discovery is a significant advance in the art of cancer therapy by providing a CDK2 inhibitor that can provoke responses in a KRAS mutant cancer to CDK4 / 6 inhibitor therapies.

[0020] The CDK2 inhibitor compound INX-315 can be used, for example, in conjunction with a CDK4 / 6 inhibitor to treat KRAS mutant cancer including but not limited to ribociclib (Novartis), abemaciclib (Eli Lilly), palbociclib (Pfizer Inc.), or lerociclib (G1 Therapeutics, Inc.; licensed to Pepper Bio, Inc.). In some embodiments, INX-315 is administered on a daily basis, and the CDK4 / 6 inhibitor is typically administered for 21 days during a 28-day cycle with a 7-day drug holiday (if ribociclib, abemaciclib or palbociclib) or with a holiday or daily (if lerociclib). In a nonlimiting embodiment, INX-315 and lerociclib can be administered on a daily, consistent basis to treat a KRAS mutant cancer.

[0021] In a second aspect, improved compositions and methods have been surprisingly discovered that include the use of an effective amount of INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a RAS inhibitor, or a pharmaceutically acceptable salt thereof, in a manner that is effective in delaying acquired resistance to RAS inhibitors in KRAS mutant cancer. It is known that tumors that are treated with RAS inhibitors develop bypass inhibitory mechanisms. However, it is now discovered that INX- 315 is able to delay the development of acquired resistance to a RAS inhibitor. For example, and as described in Example 6, the combination of INX-315 and RAS inhibitor substantially reduced cell colony outgrowth compared to the RAS inhibitor treatment alone (see, e.g., FIG. 8A-8C). In some cases, the combination of INX-315 and RAS inhibitor eliminated cell colonies altogether (see, e.g., FIG. 8C). As shown in Example 6, the combination of INX-315 and a RAS inhibitor exhibits dramatically improved cell sensitivity compared to single RAS inhibitor treatment alone, which indicates INX-315 combination treatments delay the acquisition of RAS inhibitor resistance in KRAS mutant cell lines. Similarly, the combination of INX-315 and a CDK4 / 6 inhibitor prevent colony outgrowth at levels exceeding RAS inhibitor treatment alone, further validating the efficacy of the CDK2 inhibitor and CDK4 / 6 inhibitor combination treatments in KRAS mutant cancer. Also reported herein is the surprising discovery that the administration of the CDK2 inhibitor compound INX-315 is able to induce necrosis in KRAS mutant cancer model cells (see, e.g., Example 7, FIG. 9A-9B).

[0022] In certain embodiments, INX-315 of the present invention is used to treat a patient, typically a human, to delay acquired resistance to a KRAS inhibitor selected from Sotorasib (AMG-510; Lumakras®), adagrasib (MRTX849; Krazati®), 12VC1, ARS-1620, ARS-3248, ARS-853, AZD4785, Bi-2852, BI 1823911, D-1553, GDC-6036, JAB-21822, JDQ443, JNJ- 74699157, KRpep-2d, KS-58, LY3537982, MK-1084, MRTX1133, or SML-8-73-1.

[0023] These unexpected findings indicate that INX-315 significantly improves cell sensitivity to RAS inhibitors and suppresses the development of RAS inhibitor resistance in multiple KRAS mutant cancer cells. While not wishing to be limited to one theory, it may be that cancer cells which harbor KRAS mutations become increasingly reliant on CDK2 as a core mediator of cell cycle progression, especially as a feedback mechanism when the cancer cells are contacted with one or more RAS inhibitors (see, e.g., Example 9, FIGs. 11 A, 12A).

[0024] This discovery provides a significant advance in the art of cancer therapy by providing CDK2 inhibitor combinations that are useful for treating KRAS mutant cancers that are both naive to RAS inhibitor therapy and those that are currently being treated with RAS inhibitors prior to developing acquired resistance to the RAS inhibitor therapy.

[0025] Advantageously, it has also been discovered that the CDK2 inhibitor compound is efficacious in a variety of KRAS mutant cells (see, e.g., Table 2). For example, INX-315 combination treatments exhibited efficacy in a variety of cell lines of cancers such as colorectal cancer, lung cancer, pancreatic cancer, and stomach cancer, having KRAS mutations including, but not limited to, KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12V, KRAS G13D, and KRAS Q61H, and in some cases further comprising cyclin El (CCNE1) amplification, cyclin- dependent kinase inhibitor 2A (CDKN2A) deletion, or p53 mutation or p53 deletion mutations (see, e.g., Examples 1-6).

[0026] In certain embodiments, the invention includes the use of the CDK2 inhibitor compound INX-315 of the present invention in combination with a KRAS inhibitor selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D- 1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC- 3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL- 15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof, in an effective amount to delay acquired resistance to a RAS inhibitor in a patient having KRAS mutant cancer.

[0027] In another aspect, provided herein is a method to delay acquired resistance in a patient with a KRAS mutant cancer is provided that includes administering an effective amount of the pharmaceutical combination as described herein, to the patient, typically a human.

[0028] In a third aspect, it was surprisingly discovered that INX-315, when administered in an effective amount to treat a host having a KRAS mutant cancer, for example a human, resensitizes the KRAS mutant cancer to a RAS inhibitor, wherein the KRAS mutant cancer had previously demonstrated decreased sensitivity to a RAS inhibitor. As described in Example 6 herein, the combination ofINX-315 and RAS inhibitor substantially reduced cell colony outgrowth compared to RAS inhibitor treatment alone (see, e.g., FIG. 8A-8B) and, in some cases, eliminated cell colonies altogether (see, e.g., FIG. 8C). These findings demonstrate that the CDK2 inhibitor INX- 315 significantly improved cell sensitivity to RAS inhibitor treatment and indicates that INX-315 sensitizes KRAS mutant cell lines to RAS inhibitor treatments.

[0029] In certain embodiments, therefore, INX-315 is used in an effective amount to treat a patient having decreased sensitivity to a KRAS inhibitor selected from Sotorasib (AMG-510; Lumakras®), adagrasib (MRTX849; Krazati®), 12VC1, ARS-1620, ARS-3248, ARS-853, AZD4785, Bi-2852, BI 1823911, D-1553, GDC-6036, JAB-21822, JDQ443, JNJ-74699157, KRpep-2d, KS-58, LY3537982, MK-1084, MRTX1133, or SML-8-73-1.

[0030] This discovery provides a significant advance in the art of cancer therapy by providing the CDK2 inhibitor INX-315 in an effective amount that is useful for resensitizing KRAS mutant cancer that have demonstrated decreased sensitivity to prior or ongoing RAS inhibitor therapy.

[0031] Surprisingly, in certain embodiments, the CDK2 inhibitor compound INX-315 of the present invention can resensitize a KRAS mutant cancer which has demonstrated decreased sensitivity to a KRAS inhibitor selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX-4933, RMC-4630, RM- 018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof. In an alternative aspect, provided herein is a method to resensitize a patient with a KRAS mutant cancer that includes administering an effective amount of the pharmaceutical combination with an effective amount of INX-315 as described herein, to the patient, typically a human. In a fourth aspect, it was also discovered that compositions and methods as described herein that includes the administration of an effective amount of the CDK2 inhibitor compound INX-315 demonstrate improved efficacy in cancers having loss of function of p53. This allows p53 to be used as an exemplary biomarker for patient selection. For example, and as described in Example 5 herein, cancers having p53 loss of function exhibit a trend toward an improved response to CDK2 inhibitor compound INX-315 in combination with a RAS inhibitor. This finding indicates that the selection of a KRAS mutant cancer on the basis of the status of loss of function of p53, can predict significantly improved outcomes in response to treatments comprising INX-315.

[0032] Therefore, provided herein is a composition or a method for treating a patient having a KRAS mutant cancer, comprising: i) obtaining a tumor sample from the patient; ii) detecting whether p53 has a loss of function mutation in the sample compared with a control sample that has intact p53; iii) if the sample has p53 loss of function, then administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition or method further comprises administering an effective amount of a RAS inhibitor. In some embodiments, the RAS inhibitor is a KRAS inhibitor.

[0033] The CDK2 inhibitor compound INX-315 of the present invention, or a pharmaceutically acceptable salt thereof, in combination with either a CDK4 / 6 inhibitor or a KRAS inhibitor may be used to treat a KRAS mutant disorder such as adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LUAD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer.

[0034] In certain non-limiting embodiments, the KRAS mutant cancer comprises a missense mutation which encodes a substitution at a codon selected from glycine- 12 (G12), glycine- 13 (G13), glutamine 61 (Q61), or any combination thereof. In certain nonlimiting embodiments, the mutation encodes a missense substitution selected from KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12V, KRAS G13D, KRAS Q61H, or a combination thereof. In some embodiments, the mutation is a KRAS G12C mutation. In some embodiments, the mutation is a KRAS G12D mutation. In some embodiments, the mutation is a KRAS G12S mutation. In some embodiments, the mutation is a KRAS G12D mutation. In some embodiments, the mutation is a KRAS G12V mutation. In some embodiments, the mutation is a KRAS G12D mutation. In some embodiments, the mutation is a KRAS G12D mutation. In some embodiments, the mutation is a KRAS G13D mutation. In some embodiments, the mutation is a KRAS Q61H mutation. In some embodiments, the KRAS mutant cancer further comprises CCNE1 amplification. In some embodiments, the KRAS mutant cancer further comprises CDKN2A deletion. In some embodiments, the KRAS mutant cancer further comprises a p53 mutation or a p53 deletion.

[0035] In certain aspects, the cancer has developed one or more KRAS mutations following treatment with at least one KRAS inhibitor including but not limited to covalent inhibitors sotorasib (Lumakras®) and adagrasib (Krazati®).

[0036] In certain embodiments, the CDK2 inhibitor compound INX-315 of the present invention is used in combination with a CDK4 / 6 inhibitor to treat KRAS G12C mutant cancer. In certain embodiments, the CDK2 inhibitor compound INX-315 of the present invention is used in combination with a CDK4 / 6 inhibitor to treat KRAS G12D mutant cancer. In certain embodiments, the CDK2 inhibitor compound INX-315 of the present invention is used in combination with a CDK4 / 6 inhibitor to treat KRAS G12S mutant cancer. In certain embodiments, the CDK2 inhibitor compound INX-315 of the present invention is used in combination with a CDK4 / 6 inhibitor to treat G12V mutant KRAS cancer. In certain embodiments, the CDK2 inhibitor compound INX-315 of the present invention is used in combination with a CDK4 / 6 inhibitor to treat KRAS G13D mutant cancer. In certain embodiments, the CDK2 inhibitor compound INX-315 of the present invention is used in combination with a CDK4 / 6 inhibitor to treat KRAS Q61H mutant cancer.

[0037] In a fifth aspect, it was surprisingly discovered that INX-315 can be advantageously administered to a host, such as a human, in need thereof in combination or alternation effective amount of a CDK1 inhibitor for the treatment of a CCNE1 amplified cancer. In some embodiments, the CDK1 inhibitor is a CDK1 -specific inhibitor selected from RO-3306, CGP- 74514A, or BEY1107 (avotaciclib). In some embodiments, the CDK1 inhibitor is a pan CDK inhibitor selected from alsterpaullone, kenpaullone, CVT-313, staurosporine, JNJ-7706621, olomoucine, SU9516, CDKi277, bohemine, CYC202, 3-ATA, NU2058, purvalanol A, BMS- 265246, flavopiridol (alvocidib), roniciclib (BAY1000394), P276-00 (riviciclib), dinaciclib (SCH727965), AT7519, seliciclib (roscovitine), AG-024322, PHA-793887, R547, RGB-286638, AZD-5438, indirubin (couroupitine B), milciclib, PHA-848125AC, or indirubin-5-sulfonic acid. In some embodiments, the CDK1 inhibitor is RO-3306.

[0038] In some embodiments, the CCNE1 amplified cancer is selected from ovarian cancer, uterine cancer, uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC), ovarian cancer, ovarian serous cystadenocarcinoma (OV), sarcoma (SARC), lung cancer, lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LU AD), stomach cancer, stomach adenocarcinoma (STAD), bladder cancer, bladder urothelial carcinoma (BLCA), esophageal cancer, esophageal carcinoma (ESCA), adrenocortical carcinoma, breast cancer, breast invasive carcinoma (BRCA), pancreatic cancer, pancreatic adenocarcinoma (PAAD), fallopian tube cancer, primary peritoneal cancer liver cancer, liver hepatocellular carcinoma (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), endocervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, skin cutaneous melanoma (SKCM), glioblastoma multiforme (GBM), kidney cancer, or kidney chromophobe (KICH). In some embodiments, the CCNE1 amplified cancer is an ovarian cancer. In some embodiments, the CCNE1 amplified cancer is CDK4 / 6 inhibitor-resistant. In certain embodiments, the cancer is advanced and / or metastatic cancer. In certain embodiments, the cancer is advanced unresectable cancer. In certain embodiments, the cancer is platinum-refractory and / or platinum-resistant. In certain embodiments, the cancer has progressed following a prior standard of care regimen. In certain embodiments, the cancer has progressed following a prior standard systemic therapy. In certain embodiments, the cancer has progressed following a prior systemic anti-cancer therapy. In certain embodiments, the cancer has progressed following a prior regimen comprising a platinum analog. In certain embodiments, the cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor. In some embodiments, the CCNE1 amplified cancer is uterine cancer. In some embodiments, the CCNE1 amplified cancer is ovarian cancer. In some embodiments, the CCNE1 amplified cancer is breast cancer. In some embodiments, the CCNE1 amplified cancer is prostate cancer. In some embodiments, the CCNE1 amplified cancer is bladder cancer. In some embodiments, the CCNE1 amplified cancer is a sarcoma.

[0039] The present invention thus includes at least the following features: (a) a combination, composition and / or a method or use for treating a patient, typically a human, having a KRAS mutant cancer, comprising administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a CDK4 / 6 inhibitor;

[0040] (b) a combination, composition or a method or use for treating a patient such as a human having a KRAS mutant cancer, comprising: i) obtaining a sample from the patient; ii) detecting whether KRAS is mutated in the sample compared with a control sample; iii) if KRAS comprises a mutation, then administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof in combination with a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof;

[0041] (c) a composition or a method for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, wherein the patient has already received or will receive administration of the RAS inhibitor;

[0042] (d) a composition or a method for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a RAS inhibitor;

[0043] (e) a composition or a method for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, wherein the patient has already received or is receiving administration of the RAS inhibitor;

[0044] (f) a composition or a method for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a RAS inhibitor;

[0045] (g) a composition or a method for treating a patient having a KRAS mutant cancer that comprises loss of function of p53, comprising administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof; and (h) a composition or a method for treating a patient having a KRAS mutant cancer, comprising: i) obtaining a tumor sample from the patient; ii) detecting whether the p53 in the tumor sample has a loss of function mutation compared with a control sample; iii) if the tumor sample has p53 loss of function, then administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof;

[0046] (i) a composition or a method for treating a patient having a KRAS mutant cancer that comprises loss of function of p53, comprising administering to the patient an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a RAS inhibitor; and

[0047] (j) a pharmaceutical combination or method of use that combines comprising: i) an effective amount of CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof; and ii) an effective amount of a KRAS inhibitor selected from AMG- 10 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK- 1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI- 1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX- 4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY- 5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof;

[0048] (k) use of an effective amount of the pharmaceutical combination of embodiment (j), in the manufacture of a medicament for delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer;

[0049] (l) a composition or a method for delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer, comprising administering to the patient an effective amount of the pharmaceutical combination of embodiment (j); (m) use of an effective amount of the pharmaceutical combination of embodiment (j), in the manufacture of a medicament for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient having a KRAS mutant cancer;

[0050] (n) a composition or a method for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient having a KRAS mutant cancer, comprising administering to the patient an effective amount of the pharmaceutical combination of embodiment (j); and

[0051] (o) a composition or a method for treating a patient having a CCNE1 amplified cancer, comprising administering to the patient an effective amount of CDK2 inhibitor compound INX- 315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a CDK1 inhibitor.

[0052] BRIEF DESCRIPTION OF THE DRAWINGS

[0053] FIG. l is a dose-response curve in stomach cancer model AGS cells illustrating the ratio of CellTiter-Glo (CTG) luminescence signal for different treatment groups (INX-315 = black circle, Palbociclib (Palbo) = light gray square, Palbo + 100 nM INX-315 = right side up triangle, RAS inhibitor MRTX-1133 = upside down triangle,' RAS inhibitor MRTX-1133 + 100 nM INX-315 = diamond) compared to control on the y-axis, with the molar concentration represented on the x- axis, following a 6-day treatment period as described in Example 1.

[0054] FIGs. 2A - 2B illustrate a comparison of independent studies of dose-response curves in lung cancer model A549 cells as described in Example 2.

[0055] FIG. 2Ais a dose-response curve in non-small cell lung cancer (NSCLC) model A549 cells illustrating the ratio of CellTiter-Glo (CTG) luminescence signal for different treatment groups (Cisplatin = black diamond,' 100 nM INX-315 + Palbociclib = dark gray right side up triangle, 100 nM INX-315 + RMC-6236 = grey circle, INX-315 = dark grey square, Palbociclib = light gray upside down triangle, RMC-6236 = grey diamond) compared to control on the y-axis, with the molar concentration represented on the x-axis, following a 6-day treatment period as described in Example 2.

[0056] FIG. 2B is a dose-response curve in non-small cell lung cancer (NSCLC) model A549 cells illustrating the ratio of CellTiter-Glo (CTG) luminescence signal for different treatment groups (INX-315= black circle, Palbociclib (Palbo) = light gray square, Palbo + 100 nM INX-315 = right side up triangle,' RAS inhibitor RMC-6236 = upside down triangle, RAS inhibitor RMC-6236 + 100 nM INX-315 = diamond) compared to control on the y-axis, with the molar concentration represented on the x-axis, following a 6-day treatment period as described in Example 2.

[0057] FIGs. 3A - 3B illustrate a comparison of independent studies of dose-response curves in stomach cancer model AGS cells as described in Example 2.

[0058] FIG. 3A is a dose-response curve in stomach cancer model AGS cells illustrating the ratio of CellTiter-Glo (CTG) luminescence signal for different treatment groups (Cisplatin = black diamond, 100 nM INX-315 + Palbociclib = dark gray right side up triangle, 100 nM INX-315 + RMC-6236 = grey circle,' INX-315 = dark grey square, Palbociclib = light gray upside down triangle, RMC-6236 = grey diamond) compared to control on the y-axis, with the molar concentration represented on the x-axis, following a 6-day treatment period as described in Example 2.

[0059] FIG. 3B is a dose-response curve in stomach cancer model AGS cells illustrating the ratio of CellTiter-Glo (CTG) luminescence signal for different treatment groups (INX-315= black circle,' Palbociclib = light gray square,' Palbociclib + 100 nM INX-315 = right side up triangle, RAS inhibitor MRTX-1133 = upside down triangle, RAS inhibitor MRTX-1133 + 100 nM INX- 315 = diamond) compared to control on the y-axis, with the molar concentration represented on the x-axis, following a 6-day treatment period as described in Example 2.

[0060] FIG. 4 is an independent comparative dose-response curve study in pancreatic cancer model MIA PaCa-2 cells illustrating the ratio of CellTiter-Glo (CTG) luminescence signal for different treatment groups (Cisplatin = black diamond, 100 nM INX-315 + Palbociclib = dark gray right side up triangle, 100 nM INX-315 + RMC-6236 = grey circle, INX-315 = dark grey square, Palbociclib = light gray upside down triangle,' RMC-6236 = grey diamond) compared to control on the y-axis, with the molar concentration represented on the x-axis, following a 6-day treatment period as described in Example 2.

[0061] FIG. 5A is a dose-response curve in pancreatic cancer model MIA PaCa2 cells illustrating the ratio of CellTiter-Glo (CTG) luminescence signal for different treatment groups (INX-315 = black circle, Palbociclib = light gray square, Palbociclib + 10 nM INX-315 = right side up triangle, Palbociclib + 30 nM INX-315 = upside down triangle, Palbociclib + 100 nM INX-315 = diamond, Palbociclib + 300 nM INX-315 = open circle, Palbociclib + 1000 nM INX-315 = open light gray square) compared to control on the y-axis, with the molar concentration represented on the x-axis, following a 6-day treatment period as described in Example 3.

[0062] FIG. 5B is a dose-response curve in pancreatic cancer model Panel cells illustrating the ratio of CellTiter-Glo (CTG) luminescence signal for different treatment groups (INX-315 = black circle,' Palbociclib = light gray square, Palbociclib + 10 nM INX-315 = right side up triangle, Palbociclib + 30 nM INX-315 = upside down triangle, Palbociclib + 100 nM INX-315 = diamond, Palbociclib + 300 nM INX-315 = open circle, Palbociclib + 1000 nM INX-315 = open light gray square) compared to control on the y-axis, with the molar concentration represented on the x-axis, following a 6-day treatment period as described in Example 3.

[0063] FIG. 5C is a dose-response curve in colorectal cancer model HCT 116 cells illustrating the ratio of CellTiter-Glo (CTG) luminescence signal for different treatment groups (INX-315 = black circle, Palbociclib = light gray square,' Palbociclib + 10 nM INX-315 = right side up triangle, Palbociclib + 30 nM INX-315 = upside down triangle, Palbociclib + 100 nM INX-315 = diamond, Palbociclib + 300 nM INX-315 = open circle, Palbociclib + 1000 nM INX-315 = open light gray square) compared to control on the y-axis, with the molar concentration represented on the x-axis, following a 6-day treatment period as described in Example 3.

[0064] FIG. 6A illustrates a comparison of the pM logl0(IC50) of palbociclib vs the pM logl0(IC50) of palbociclib + 100 nM INX-315 as described in Example 4. Dotted lines show 500 nM IC50 as a marker for sensitivity to treatment. Eight cell lines become sensitive with the addition of 100 nM INX-315, with four additional cell lines having significantly decreased IC50 values by the addition of INX-315. Two cell lines that are sensitive to palbociclib have an improved response with the addition of INX-315. Cell lines A-427, LoVo, LS 513, NCI-H460, HCT 116, AGS, COR-L23, Pane 08.13, and A549 have functional p53, while the rest have p53 loss of function. Shapes represent the functional status of pl6. NCI-H358, SW-1463, NCI-H2009, T84, OVCAR-8, LoVo, SW-620, NCI-H23, and HPAF-II have functional p!6, while the rest have pl6 loss of function. NCI-H2009, OVCAR-8 and T84 are with Rb loss of function, while the rest have functional Rb.

[0065] FIG. 6B illustrates a comparison of the pM logl0(IC50) of palbociclib versus the pM logl0(IC50) of palbociclib + 100 nM INX-315 in cancer model cell lines according to cancer type as described in Example 4. The improvement in response is not dictated by cancer cell origin. FIG. 6C illustrates a comparison of the areas under the curve of palbociclib versus the areas under the curve of palbociclib + 100 nM INX-315 as described in Example 4. Cell lines A-427, LoVo, LS 513, NCI-H460, HCT 116, AGS, COR-L23, Pane 08.13, and A549 have functional p53, while the rest have p53 loss of function. Shapes represent the functional status of pl6. NCI-H358, SW-1463, NCI-H2009, T84, OVCAR-8, LoVo, SW-620, NCI-H23, and HPAF-II have functional pl 6, while the rest have pl6 loss of function. NCI-H2009, OVCAR-8 and T84 are with Rb loss of function, while the rest have functional Rb.

[0066] FIG. 7A illustrates the ratio of the area under the curves (AUC) of RMC-6236 + 100 nM INX-315 over RMC-6236 alone based upon Rb status as described in Example 5. Numbers less than one indicate INX-315 improved the efficacy of RMC-6236. The x-axis splits cell lines by the functional status of Rb.

[0067] FIG. 7B illustrates the ratio of the area under the curves (AUC) of RMC-6236 + 100 nM INX-315 over RMC-6236 alone based upon pl6 status as described in Example 5. Numbers less than one indicate INX-315 improved the efficacy of RMC-6236. The x-axis splits cell lines by the functional status of pl 6.

[0068] FIG. 7C illustrates the ratio of the area under the curves (AUC) of RMC-6236 + 100 nM INX-315 over RMC-6236 alone based upon p53 status as described in Example 5. Numbers less than one indicate INX-315 improved the efficacy of RMC-6236. The x-axis splits cell lines by the functional status of p53. Cells with loss of p53 more often benefit from combination with INX- 315.

[0069] FIG. 8A show culture plate images taken during a crystal violet colony assay showing INX- 315 (315) delays outgrowth of cells treated with RAS inhibitor (RASi) RMC-6236, with the combination of INX-315 and CDK4 / 6 inhibitor Palbociclib (P) reducing cell growth greater than other treatments. Experimental conditions for this experiment are found in Example 6. Colorectal cancer model HCT 116 cell colonies were treated with either RAS inhibitor RMC-6236 alone or INX-315 in combination with RMC-6236 or the CDK4 / 6 inhibitor palbociclib compared to mock control.

[0070] FIG. 8B show culture plate images taken during a crystal violet colony assay showing INX- 315 (315) delays outgrowth of cells treated with RAS inhibitor RMC-6236 (RASi), with the combination of INX-315 and CDK4 / 6 inhibitor Palbociclib (P) reducing cell growth greater than other treatments. Experimental conditions for this experiment are found in Example 6. Non-small cell lung cancer (NSCLC) model A549 cell colonies were treated with either RAS inhibitor RMC- 6236 alone or INX-315 in combination with RMC-6236 or the CDK4 / 6 inhibitor palbociclib compared to mock control.

[0071] FIG. 8C show culture plate images taken during a crystal violet colony assay showing both combination groups containing INX-315 (315) eliminated all cell colonies. Experimental conditions for this experiment are found in Example 6. Pancreatic cancer model MIAPaCa2 cell colonies were treated with either RAS inhibitor (RASi) RMC-6236 alone or INX-315 in combination with RMC-6236 or the CDK4 / 6 inhibitor Palbociclib (P) compared to mock control.

[0072] FIG. 9A illustrates the ratio of necrotic colorectal cancer model HCT 116 cells in different treatment groups (INX-315 (315)= black circle,' RAS inhibitor (RAS)= light gray square,' RAS inhibitor + INX-315 (RAS + 315) = right side up triangle, Palbociclib (Palbo) = upside down triangle, Palbociclib + INX-315 (Palbo + 315) = diamond) compared to control represented on the y-axis, with the molar concentration represented on the x-axis, following a 48-hour treatment period as described in Example 7.

[0073] FIG. 9B illustrates the ratio of necrotic colorectal cancer model HCT 116 cells in different treatment groups (INX-315 (315) = black circle,' RAS inhibitor (RAS) = light gray square, RAS inhibitor + INX-315 (RAS + 315) = right side up triangle, Palbociclib (Palbo) = upside down triangle, Palbociclib + INX-315 (Palbo + 315) = diamond) compared to control represented on the y-axis, with the molar concentration represented on the x-axis, following a 48-hour treatment period as described in Example 7.

[0074] FIG. 10A is a bar graph that demonstrates the percent of pancreatic cancer model MIA PaCa2 cells in certain cell cycle phases including the G1 phase, the S phase, the G2 / M phase, as well as <2N cells on the y-axis for different treatment groups represented on the x-axis as described in Example 8. RAS inhibitor, RASi; Palbociclib, Palbo.

[0075] FIG. 1 OB is a bar graph that demonstrates the percent of stomach cancer model AGS cells in certain cell cycle phases including the G1 phase, the S phase, the G2 / M phase, as well as <2N cells on the y-axis for different treatment groups represented on the x-axis as described in Example 8. RAS inhibitor, RASi; Palbociclib, Palbo. FIG. IOC is a bar graph that demonstrates the percent of colorectal cancer model HCT 116 cells in certain cell cycle phases including the G1 phase, the S phase, the G2 / M phase, as well as <2N cells on the y-axis for different treatment groups represented on the x-axis as described in Example 8. RAS inhibitor, RASi; Palbociclib, Palbo.

[0076] FIG. HA is a western blot showing levels of markers of phosphorylated retinoblastoma (pRb) protein (pRb S807 / 811), retinoblastoma (Rb) protein, cyclin proteins (Cyclin El, Cyclin A2), and a marker of apoptosis (Survivin) compared to loading control (GAPDH) in stomach cancer model AGS cells for different treatment groups as described in Example 9. Control, C; INX-315, 315; Palbociclib, Palbo; RAS inhibitor, RASi or R.

[0077] FIG. 11B is a western blot showing levels of markers of phosphorylated cell cycle- associated proteins (pT600 FoxMl, pT48 CDC25c, pAkt, pMEK, and pERK) and total levels of cell cycle-associated proteins (Akt, MEK) in stomach cancer model AGS cells for different treatment groups as described in Example 9. Control, C; INX-315, 315; Palbociclib, Palbo; RAS inhibitor, RASi or R.

[0078] FIG. 12A is a western blot showing levels of markers of phosphorylated retinoblastoma (pRb) protein (pRb S807 / 811), retinoblastoma (Rb) protein, cyclin proteins (Cyclin El, Cyclin A2), and a marker of apoptosis (Survivin) compared to loading control (GAPDH) in colorectal cancer model HCT 116 cells for different treatment groups as described in Example 9. Control, C; INX-315, 315; Palbociclib, Palbo; RAS inhibitor, RASi or R.

[0079] FIG. 12B is a western blot showing levels of markers of phosphorylated cell cycle- associated proteins (pT600 FoxMl, pT48 CDC25c, pAkt, pMEK, and pERK) and total levels of cell cycle-associated proteins (Akt, MEK) in colorectal cancer model HCT 116 cells for different treatment groups as described in Example 9. Control, C; INX-315, 315; Palbociclib, Palbo; RAS inhibitor, RASi or R.

[0080] DETAILED DESCRIPTION

[0081] Terminology

[0082] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0083] The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and / or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0084] In some embodiments, the term “about” means ± 10%.

[0085] The term “mutation” as used herein refers to any modification of a nucleic acid which results in an altered or modified nucleic acid. The term “mutation” can include, for example, point mutations, deletions, insertions, or amplifications of single or multiple residues in a polynucleotide. In some embodiments, the mutation includes modifications of a protein coding sequence of a gene but can also include modifications in regions outside of the protein coding sequence, for example promoter sequences.

[0086] “Acquired resistance,” as used herein, refers to a condition wherein a cancer that was or is initially sensitive to the inhibitory effects of an anti -cancer therapy becomes non-responsive or less-responsive over time to the effects of the administration of that therapy. In some embodiments of the methods described herein, the cancer to be treated has acquired resistance to a selective CDK4 / 6 inhibitor. Without wishing to be bound by any one theory, it is believed that acquired resistance to RAS inhibitors occurs due to one or more additional mutations or genetic alterations in bypass signaling that develops after the onset of a RAS inhibitor treatment regimen. For example, non-limiting exemplary causes of acquired resistance to RAS inhibitors may be a result of the development of one or more genetic aberrations associated with “intrinsic resistance”. In addition, other non-limiting exemplary causes of acquired resistance to RAS inhibitors may include ERK-mediated feedback inhibition, development of secondary KRAS mutations, reactivation of KRAS through activation of receptor tyrosine kinases (RTKs), PI3K activation by the IGFR-IRS1 pathway, ErbB signaling activation, as well as simultaneously converging resistance mechanisms; or a combination thereof. A general review of RAS-resistance mechanisms can be found, for example, in Dunnett-Kane, V. et al. Mechanisms of Resistance to KRASG12C Inhibitors. Cancers (Basel). 13(1 ): 151 (2021 Jan 5), incorporated herein by reference. In some embodiments, a tumor or cancer that has acquired resistance to RAS inhibition is a tumor or cancer whose cell population, as a whole, no longer exhibits substantial binding of the GDP- bound KRAS protein therein to a RAS inhibitor, resulting in disease progression. In some embodiments, the cancer has progressed following a prior therapeutic regimen comprising the administration of a RAS inhibitor. In some alternative embodiments of the methods of treatment described herein, the cancer treated has acquired resistance, for example to an CDK4 / 6 inhibitor therapy such as but not limited to, palbociclib, riboci clib, or abemaciclib. In some alternative embodiments of the methods of treatment described herein, the cancer treated has acquired resistance to an additional anti-cancer therapy.

[0087] The “patient” or “patient” or “participant” treated is typically a human patient, unless otherwise indicated. In alternative embodiments, the methods described herein can be used to treat or in testing of other animals that respond similarly, such as mammals, for example, such as those used in preclinical testing including but not limited to mice, rats, monkeys, dogs, pigs, and rabbits; as well as domesticated swine (pigs and hogs), ruminants, equine, poultry, felines, bovines, murines, canines, and the like.

[0088] INX-315 and CDK4 / 6 Inhibitor Combinations Effectively Treat KRAS Mutant Cancer

[0089] In one aspect, provided herein are compositions and methods for treating a patient having a KRAS mutant cancer, comprising administering to the patient an effective amount of the cyclin dependent kinase 2 (CDK2) inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is lerociclib.

[0090] In another aspect, provided herein are compositions and methods for treating a patient having a KRAS mutant cancer, comprising administering to the patient an effective amount of the cyclin dependent kinase 2 (CDK2) inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is lerociclib.

[0091] In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS G12 substitution is a KRAS G12C substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12D substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12S substitution. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the KRAS substitution is a KRAS DI 62 substitution. In some embodiments, the KRAS DI 62 substitution is a KRAS D162K substitution. In some embodiments, the KRAS mutant cancer comprises a KRAS amplification. In some embodiments, the KRAS mutant cancer further comprises cyclin El (CCNE1) overexpression or amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant cancer further comprises loss of function of p53. In some embodiments, the KRAS mutant cancer further comprises cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion.

[0092] In some embodiments, the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer. In some embodiments, the KRAS mutant cancer is colorectal cancer. In some embodiments, the KRAS mutant cancer is non-small cell lung cancer (NSCLC). In some embodiments, the KRAS mutant cancer is pancreatic cancer.

[0093] In another aspect, provided herein are compositions and methods for treating a patient having a KRAS mutant stomach cancer, comprising administering to the patient an effective amount of the cyclin dependent kinase 2 (CDK2) inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPL16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP- 3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is lerociclib. In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS G12 substitution is a KRAS G12D substitution. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS mutant stomach cancer comprises a KRAS amplification. In some embodiments, the KRAS mutant stomach cancer further comprises cyclin El (CCNE1) overexpression or amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant stomach cancer further comprises loss of function of p53. In some embodiments, the KRAS mutant stomach cancer further comprises cyclin-dependent kinase inhibitor 2 A (CDKN2A) deletion.

[0094] In another aspect, provided herein are compositions and methods for treating a patient having a KRAS mutant NSCLC, comprising administering to the patient an effective amount of the cyclin dependent kinase 2 (CDK2) inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP- 3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is lerociclib. In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS G12 substitution is KRAS G12D. In some embodiments, the KRAS G12 substitution is G12S. In some embodiments, the KRAS G12 substitution is 12V. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS Q61 substitution is KRAS Q61H. In some embodiments, the KRAS mutant NSCLC comprises a KRAS amplification. In some embodiments, the KRAS mutant NSCLC further comprises cyclin El (CCNE 1) overexpression or amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant NSCLC further comprises loss of function of p53. In some embodiments, the KRAS mutant NSCLC further comprises cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion.

[0095] In another aspect, provided herein are compositions and methods for treating a patient having a KRAS mutant pancreatic cancer, comprising administering to the patient an effective amount of the cyclin dependent kinase 2 (CDK2) inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP- 3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is lerociclib. In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS G12 substitution is KRAS G12C. In some embodiments, the KRAS G12 substitution is KRAS G12D. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS mutant pancreatic cancer comprises a KRAS amplification. In some embodiments, the KRAS mutant pancreatic cancer further comprises cyclin El (CCNE1) overexpression or amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant pancreatic cancer further comprises loss of function of p53. In some embodiments, the KRAS mutant pancreatic cancer further comprises cyclin-dependent kinase inhibitor 2 A (CDKN2A) deletion. In another aspect, provided herein are compositions and methods for treating a patient having a KRAS mutant colorectal cancer, comprising administering to the patient an effective amount of the cyclin dependent kinase 2 (CDK2) inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP- 3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is lerociclib. In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or aKRAS D162 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS G13 substitution is a KRAS G13D substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS mutant colorectal cancer comprises a KRAS amplification. In some embodiments, the KRAS mutant colorectal cancer further comprises cyclin El (CCNE1) overexpression or amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant colorectal cancer further comprises loss of function of p53. In some embodiments, the KRAS mutant colorectal cancer further comprises cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion.

[0096] In some embodiments, the KRAS mutant cancer is of the breast, central nervous system, cervix, colon, colorectal, endocrine system, core gastrointestinal tract, accessory gastrointestinal tract, hematological system, head and neck, lung, pancreas, skin, stomach, testis, thoracic, or uterus. In some embodiments, the KRAS mutant cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, anaplastic thyroid carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, cholangiocarcinoma, chronic myeloid leukemia, colon adenocarcinoma, endocervical adenocarcinoma, endometrial carcinoma, esophageal carcinoma, follicular thyroid carcinoma, glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSCC), kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lower grade glioma, lung adenocarcinoma, lung squamous cell carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, papillary thyroid carcinoma, plasma cell myeloma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin cutaneous melanoma, small intestine adenocarcinoma, stomach adenocarcinoma, testicular germ cell tumors, uterine carcinosarcoma, or uterine corpus liver hepatocellular carcinoma. In some embodiments, the cancer is NSCLC. In an alternative embodiment, the cancer harboring a KRAS mutation encoding a G12D substitution is colon adenocarcinoma, pancreatic adenocarcinoma, rectum adenocarcinoma, or uterine corpus endometrial carcinoma. In some embodiments, the cancer harboring a KRAS mutation encoding a G12C substitution is lung adenocarcinoma or rectum adenocarcinoma. In some embodiments, the cancer harboring a KRAS mutation encoding a G12V substitution is colon adenocarcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, rectum adenocarcinoma, or uterine carcinosarcoma. In some embodiments, the cancer harboring a KRAS mutation encoding a G12S substitution is colon adenocarcinoma or rectum adenocarcinoma. In some embodiments, the cancer harboring a KRAS mutation encoding a Q61K substitution is cholangiocarcinoma or colon adenocarcinoma.

[0097] In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a RAS inhibitor. In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

[0098] In one aspect, provided herein are compositions and methods for sensitizing a KRAS mutant cancer to a CDK4 / 6 inhibitor therapy, comprising administering to the patient an effective amount of the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, in addition to or alternation with the CDK4 / 6 inhibitor therapy. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is lerociclib.

[0099] In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS G12 substitution is a KRAS G12C substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12D substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12S substitution. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the KRAS substitution is a KRAS DI 62 substitution. In some embodiments, the KRAS DI 62 substitution is a KRAS D162K substitution. In some embodiments, the KRAS mutant cancer comprises a KRAS amplification.

[0100] In some embodiments, the KRAS mutant cancer further comprises cyclin El (CCNE1) overexpression or amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant cancer further comprises loss of function of p53. In some embodiments, the KRAS mutant cancer further comprises cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion.

[0101] In some embodiments, the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer. In some embodiments, the KRAS mutant cancer is colorectal cancer. In some embodiments, the KRAS mutant cancer is non-small cell lung cancer (NSCLC). In some embodiments, the KRAS mutant cancer is pancreatic cancer. In another aspect, provided herein are compositions and methods for treating a patient having a KRAS mutant cancer, comprising: (i) obtaining a sample from the patient; (ii) detecting whether KRAS is mutated in the sample compared with a control sample; (iii) if KRAS comprises a mutation, then administering to the patient: (a) an effective amount of the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof; and (b) an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, biroci clib (XZP-3287), LY5219, PF-07220060, or ON- 123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib.

[0103] In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or aKRAS D162 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS G12 substitution is a KRAS G12C substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12D substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12S substitution. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the KRAS substitution is a KRAS DI 62 substitution. In some embodiments, the KRAS DI 62 substitution is a KRAS D162K substitution. In some embodiments, the KRAS mutant cancer comprises a KRAS amplification.

[0104] In some embodiments, the KRAS mutant cancer further comprises CCNE1 amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant cancer further comprises cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion.

[0105] In some embodiments, the KRAS mutant cancer comprises loss of function of p53. In some embodiments, the loss of function p53 mutation comprises a mutation in a codon which encodes a p53 residue selected from R175, G245, R248, R249, R273, or R282. In some embodiments, the loss of function of p53 comprises p53 deletion.

[0106] In some embodiments, the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer. In some embodiments, the KRAS mutant cancer is colorectal cancer. In some embodiments, the KRAS mutant cancer is non-small cell lung cancer (NSCLC). In some embodiments, the KRAS mutant cancer is pancreatic cancer. In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a RAS inhibitor. In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

[0107] In some embodiments, the KRAS mutant cancer further comprises CCNE1 amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant cancer further comprises cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion.

[0108] In some embodiments, INX-315 is administered in a dosage form between about 100 mg and about 800 mg. In some embodiments, INX-315 is administered in a dosage form selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, INX-315 is administered at least once a day. In some embodiments, INX- 315 is continuously administered for at least 21 days, at least 24 days, at least 28 days, at least 35 days, or more than 35 days.

[0109] In some embodiments, the RAS mutation is determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO / Reveal Dx Lung & Colon Cancer Assay (O / RDx-LCC A), therascreen KRAS RGQ PCR Kit, Praxis Extended RAS Panel, or a combination thereof.

[0110] In some embodiments, the method results in an improved lifespan for the patient as compared to the lifespan of a control patient that has not received a treatment with INX-315.

[0111] In some embodiments, the patient is a human. INX-315 Delays Resistance to RAS Inhibitors in KRAS Mutant Cancer

[0112] In an alternative aspect, provided herein are compositions and methods for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, wherein the patient has already received, will receive administration of, or is receiving the RAS inhibitor.

[0113] In some embodiments, the method further comprises administering to the patient an effective amount of a RAS inhibitor. In some embodiments, the RAS inhibitor is a KRAS inhibitor. In some embodiments, the KRAS inhibitor is a small molecule KRAS inhibitor. In some embodiments, the small molecule KRAS inhibitor has a molecular weight of less than about 2,000 Daltons. In some embodiments, the KRAS inhibitor binds to or is selective for KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G12R. In some embodiments, the KRAS inhibitor binds to or is selective for KRAS Q61H, KRAS Q61R, KRAS Q61L, KRAS Q61K, KRAS Q61P, or KRAS Q61E. In some embodiments, the KRAS inhibitor is a pan-KRAS inhibitor. In some embodiments, the KRAS inhibitor is an inhibitor of GDP -bound KRAS. In some embodiments, the GDP -bound KRAS inhibitor is selected from RM-018, RMC-6291, RMC- 6236, BI-2852, BI-2493, BI-0474, or BI-2865.

[0114] In certain embodiments, the KRAS inhibitor has at least about 2-fold, at least about 5 -fold, at least about 10-fold or even at least about 25-fold selectivity for a particular KRAS mutant, such as a mutant KRAS with a substitution at position 12 or 13, including but not limited to KRAS G12C, G12D, G12V, G12S, G12A, G12R, and G13. In certain embodiments, the KRAS inhibitor is a pan-KRAS inhibitor. In certain embodiments, the KRAS inhibitor has less than 10-fold, less than 5-fold, or less than 2-fold selectivity for a particular KRAS mutant form over other forms of KRAS such as other mutant forms and / or wild-type KRAS.

[0115] In some embodiments, the KRAS inhibitor is selected from AMG-510 (sotorasib), MRTX- 849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI- 1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001 , BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX-4933, RMC- 4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY-5933, BBO- 8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the KRAS inhibitor is selected from or a pharmaceutically acceptable salt thereof.

[0117] In certain embodiments, the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, can be used in an effective amount in combination or alternation with a compound selected from Sotorasib (AMG-510; Lumakras®), adagrasib (MRTX849; Krazati®), 12VC1, ARS-1620, ARS-3248, ARS-853, AZD4785, Bi-2852, BI 1823911, D-1553, GDC-6036, JAB-21822, JDQ443, JNJ-74699157, KRpep-2d, KS-58, LY3537982, MK-1084, MRTX1133, and SML-8-73-1, for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, wherein the patient has already received or is receiving the RAS inhibitor.

[0118] In certain embodiments, the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, can be used in an effective amount in combination or alternation with a compound selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX- EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI- 421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB- 21000, HS-10370 IBL351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX-4933, YL-15293, GEC255, SY-5933, BBO-8520, RMC- 9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, and RMC-4630, for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, wherein the patient has already received or is receiving the RAS inhibitor.

[0119] In certain embodiments, the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, can be used in an effective amount in combination or alternation with an inhibitor of GDP -bound KRAS. In certain embodiments the GDP -bound KRAS inhibitor is selected from RM-018, RMC-6291, RMC-6236, BI-2852, BL2493, or BI-2865.

[0120] In certain embodiments, the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, can be used in combination or alternation with an inhibitor of S0S1 or an inhibitor of SOS1-KRAS binding. In certain embodiments, the S0S1 inhibitor is MRTX0902, BI 1701963, BAY-293, or BI-3406.

[0121] In certain embodiments, the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, is used in an effective amount in combination or alternation with a KRAS inhibitor of the structure: or a pharmaceutically acceptable salt thereof, wherein

[0122] ( ' —A ) is selected from heterocycle, heteroaryl, and aryl;

[0123] Q is selected from heterocycle, cycloalkyl, aryl, heteroaryl, bicycle, -NR10-heterocycle, -NR10-cycloalkyl, -NR10-aryl, -NR10-heteroaryl, -NR10-bicycle, -O-heterocycle, -O-cycloalkyl, -O-aryl, -O-heteroaryl, and -O-bicycle, optionally substituted by oxo, Ci-salkyl, C2-4alkynyl, heteroalkyl, cyano, -C(O)OR5, -C(O)N(R5)2, -N(R5)2, wherein the Ci-salkyl may be optionally substituted with cyano, halogen, -OR5, -N(R5)2, or heteroaryl; R1is selected from hydrogen, -C(O)-ethylene, -C(O)-ethynyl, -S(O)-ethylene, -S(O)-ethynyl, -SCh-ethylene, and -SCh-ethynyl;

[0124] Y is bond, Ci-4alkylene, -O-, -NR10-, -S-, -S(O)-, -S(O)2-, or -C(O)-;

[0125] R2is hydrogen, alkyl, -Z-NR5R10, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R9;

[0126] Z is Ci-4alkyl;

[0127] R4is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from R6and R7;

[0128] R?is independently selected at each instance from hydrogen and Ci-salkyl;

[0129] R6is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R7; each R7is independently halogen, hydroxyl, Ci-ealkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, -O-haloalkyl, or -S-haloalkyl; in certain embodiments R9is hydrogen; in certain embodiments each R9is independently halogen, hydroxyl, Ci-ealkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, -O-haloalkyl, or -S-haloalkyl; in certain embodiments L is bond; in certain embodiments L is cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from R6and R7; in certain embodiments each R9is independently halogen, hydroxyl, Ci-ealkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl, -O-haloalkyl, or -S-haloalkyl; and

[0130] R10is independently hydrogen, acyl, Ci-3alkyl, heteroalkyl or hydroxyalkyl.

[0131] In another aspect, provided herein are compositions and methods for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, and an effective amount of a KRAS inhibitor selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPL421286, GH35, BEBT-607, LY3499446, MK- 1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI- 1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX- 4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY- 5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer. In some embodiments, the KRAS mutant cancer is colorectal cancer. In some embodiments, the KRAS mutant cancer is non-small cell lung cancer (NSCLC). In some embodiments, the KRAS mutant cancer is pancreatic cancer. In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a RAS inhibitor. In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

[0133] In some embodiments, the KRAS mutant cancer is of the breast, central nervous system, cervix, colon, colorectal, endocrine system, core gastrointestinal tract, accessory gastrointestinal tract, hematological system, head and neck, lung, pancreas, skin, stomach, testis, thoracic, or uterus. In some embodiments, the KRAS mutant cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, anaplastic thyroid carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, cholangiocarcinoma, chronic myeloid leukemia, colon adenocarcinoma, endocervical adenocarcinoma, endometrial carcinoma, esophageal carcinoma, follicular thyroid carcinoma, glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSCC), kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lower grade glioma, lung adenocarcinoma, lung squamous cell carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, papillary thyroid carcinoma, plasma cell myeloma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin cutaneous melanoma, small intestine adenocarcinoma, stomach adenocarcinoma, testicular germ cell tumors, uterine carcinosarcoma, or uterine corpus liver hepatocellular carcinoma.

[0134] In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS G12 substitution is a KRAS G12C substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12D substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12S substitution. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the KRAS substitution is a KRAS D162 substitution. In some embodiments, the KRAS DI 62 substitution is a KRAS D162K substitution. In some embodiments, the KRAS mutant cancer comprises a KRAS amplification.

[0135] In some embodiments, the KRAS mutant cancer further comprises cyclin El (CCNE1) overexpression or amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant cancer further comprises loss of function of p53. In some embodiments, the KRAS mutant cancer further comprises cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion.

[0136] In some embodiments, the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer. In some embodiments, the KRAS mutant cancer is colorectal cancer. In some embodiments, the KRAS mutant cancer is non-small cell lung cancer (NSCLC). In some embodiments, the KRAS mutant cancer is pancreatic cancer. In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor. In some embodiments, the method results in tumor necrosis.

[0137] In some embodiments, INX-315 is administered in a dosage form between about 100 mg and about 800 mg. In some embodiments, INX-315 is administered in a dosage form selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, INX-315 is administered at least once a day. In some embodiments, INX- 315 is continuously administered for at least 21 days, at least 24 days, at least 28 days, at least 35 days, or more than 35 days.

[0138] In some embodiments, the RAS mutation is determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO / Reveal Dx Lung & Colon Cancer Assay (O / RDx-LCCA), therascreen KRAS RGQ PCR Kit, Praxis Extended RAS Panel, or a combination thereof.

[0139] In some embodiments, the method results in an improved lifespan for the patient as compared to the lifespan of a control patient that has not received a treatment with INX-315.

[0140] In some embodiments, the patient is a human.

[0141] INX-315 Resensitizes KRAS Mutant Cancers to RAS Inhibitors

[0142] In an additional aspect, provided herein are compositions and methods for resensitizing a KRAS mutant cancer to a RAS inhibitor, comprising administering CDK2 inhibitor INX-315, or a pharmaceutically acceptable salt thereof, to a patient having a KRAS mutant cancer, wherein the KRAS mutant cancer has demonstrated decreased sensitivity to a RAS inhibitor. In certain embodiments, the method further comprises administering an effective amount of a KRAS inhibitor selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX- EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI- 421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB- 21000, HS-10370 IBL351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI- 2852, BI-2493, YL-15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or B 1-2865, or a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, INX-315 of the present invention is used to treat a patient having a KRAS mutant cancer having decreased sensitivity to a KRAS inhibitor selected from Sotorasib (AMG-510; Lumakras®), adagrasib (MRTX849; Krazati®), 12VC1, ARS-1620, ARS-3248, ARS-853, AZD4785, Bi-2852, BI 1823911, D-1553, GDC-6036, JAB-21822, JDQ443, JNJ- 74699157, KRpep-2d, KS-58, LY3537982, MK-1084, MRTX1133, or SML-8-73-1.

[0144] In some embodiments, the method further comprises administering to the patient an effective amount of a RAS inhibitor. In some embodiments, the RAS inhibitor is a KRAS inhibitor. In some embodiments, the KRAS inhibitor is a small molecule KRAS inhibitor. In some embodiments, the small molecule KRAS inhibitor has a molecular weight of less than about 2,000 Daltons. In some embodiments, the KRAS inhibitor binds to or is selective for KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G12R. In some embodiments, the KRAS inhibitor binds to or is selective for KRAS Q61H, KRAS Q61R, KRAS Q61L, KRAS Q61K, KRAS Q61P, or KRAS Q61E. In some embodiments, the KRAS inhibitor is a pan-KRAS inhibitor. In some embodiments, the KRAS inhibitor is an inhibitor of GDP -bound KRAS. In some embodiments, the GDP -bound KRAS inhibitor is selected from RM-018, RMC-6291, RMC- 6236, BI-2852, BI-2493, BL0474, or BI-2865.

[0145] In certain embodiments, the KRAS inhibitor has at least about 2-fold, at least about 5 -fold, at least about 10-fold or even at least about 25-fold selectivity for a particular KRAS mutant, such as a mutant KRAS with a substitution at position 12 or 13, including but not limited to KRAS G12C, G12D, G12V, G12S, G12A, G12R, and G13. In certain embodiments, the KRAS inhibitor is a pan-KRAS inhibitor. In certain embodiments, the KRAS inhibitor has less than 10-fold, less than 5-fold, or less than 2-fold selectivity for a particular KRAS mutant form over other forms of KRAS such as other mutant forms and / or wild-type KRAS. In some embodiments, the KRAS inhibitor is selected from AMG-510 (sotorasib), MRTX- 849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI- 1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX-4933, RMC- 4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY-5933, BBO- 8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the KRAS inhibitor is selected from or a pharmaceutically acceptable salt thereof.

[0147] In certain embodiments, the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof, can be used in an effective amount in combination or alternation with a compound selected from Sotorasib (AMG-510; Lumakras®), adagrasib (MRTX849; Krazati®), 12VC1, ARS-1620, ARS-3248, ARS-853, AZD4785, Bi-2852, BI 1823911, D-1553, GDC-6036, JAB-21822, JDQ443, JNJ-74699157, KRpep-2d, KS-58, LY3537982, MK-1084, MRTX1133, and SML-8-73-1, for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, wherein the patient has already received or is receiving the RAS inhibitor. In some embodiments, the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer. In some embodiments, the KRAS mutant cancer is colorectal cancer. In some embodiments, the KRAS mutant cancer is non-small cell lung cancer (NSCLC). In some embodiments, the KRAS mutant cancer is pancreatic cancer. In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a RAS inhibitor. In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

[0148] In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS G12 substitution is a KRAS G12C substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12D substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12S substitution. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the KRAS substitution is a KRAS D162 substitution. In some embodiments, the KRAS DI 62 substitution is a KRAS D162K substitution. In some embodiments, the KRAS mutant cancer comprises a KRAS amplification.

[0149] In some embodiments, pharmaceutical combinations as described herein comprising the CDK2 inhibitor compound INX-315 of the present invention are administered to resensitize a KRAS mutant cancer having decreased sensitivity to a KRAS inhibitor selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPL421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D- 1553 (garsorasib), HBL2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBT-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC- 3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BL2493, YL-15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865. In an alternative aspect, provided herein is a method to resensitize a patient to a RAS inhibitor with a KRAS mutant cancer that includes administering an effective amount of the pharmaceutical combination as described herein, to the patient, typically a human.

[0150] In some embodiments, INX-315 is administered in a dosage form between about 100 mg and about 800 mg. In some embodiments, INX-315 is administered in a dosage form selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, INX-315 is administered at least once a day. In some embodiments, INX- 315 is continuously administered for at least 21 days, at least 24 days, at least 28 days, at least 35 days, or more than 35 days.

[0151] In some embodiments, the RAS mutation is determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO / Reveal Dx Lung & Colon Cancer Assay (O / RDx-LCCA), therascreen KRAS RGQ PCR Kit, Praxis Extended RAS Panel, or a combination thereof.

[0152] In some embodiments, the method results in an improved lifespan for the patient as compared to the lifespan of a control patient that has not received a treatment with INX-315.

[0153] In some embodiments, the patient is a human.

[0154] Biomarkers that Predict Efficacy of INX-315 in KRAS Mutant Cancer

[0155] In yet another aspect, provided herein are compositions and methods for treating a patient having a KRAS mutant cancer comprising loss of function of p53, comprising administering to the patient an effective amount of the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof. In some embodiments, the loss of function of p53 comprises a p53 mutation. In some embodiments, the loss of function p53 mutation comprises a mutation in a codon which encodes a p53 residue selected from R175, G245, R248, R249, R273, or R282. In some embodiments, the loss of function of p53 comprises p53 deletion.

[0156] In an additional aspect, disclosed herein is a methods for treating a patient with a KRAS mutant cancer, comprising monitoring a sample of the patient for p53 loss of function compared with a control sample, wherein, upon determining a patient has p53 loss of function, administering to the patient an effective amount of INX-315, or a pharmaceutically acceptable salt thereof. In some embodiments, the loss of function of p53 comprises a p53 mutation. In some embodiments, the loss of function p53 mutation comprises a mutation in a codon which encodes a p53 residue selected from R175, G245, R248, R249, R273, or R282. In some embodiments, the loss of function of p53 comprises p53 deletion.

[0157] In some embodiments, the method further comprises administering to the patient an effective amount of a RAS inhibitor. In some embodiments, the RAS inhibitor is a KRAS inhibitor. In some embodiments, the KRAS inhibitor binds to or is selective for KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G12R. In some embodiments, the KRAS inhibitor binds to oris selective for KRAS Q61H, KRAS Q61R, KRAS Q61L, KRAS Q61K, KRAS Q61P, or KRAS Q61E. In some embodiments, the KRAS inhibitor is a pan-KRAS inhibitor. In some embodiments, the KRAS inhibitor is an inhibitor of GDP -bound KRAS. In some embodiments, the GDP-bound KRAS inhibitor is selected from RM-018, RMC-6291, RMC-6236, BI-2852, BI- 2493, BI-0474, or BI-2865. In some embodiments, the KRAS inhibitor is selected from AMG- 510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ- 74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D- 1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC- 3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL- 15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is selected from or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the KRAS mutant cancer comprises a mutation encoding a KRAS substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution. In some embodiments, the KRAS substitution is a KRAS G12 substitution. In some embodiments, the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. In some embodiments, the KRAS G12 substitution is a KRAS G12C substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12D substitution. In some embodiments, the KRAS G12 substitution is a KRAS G12S substitution. In some embodiments, the KRAS substitution is a KRAS G13 substitution. In some embodiments, the KRAS substitution is a KRAS Q61 substitution. In some embodiments, the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the KRAS substitution is a KRAS D162 substitution. In some embodiments, the KRAS DI 62 substitution is a KRAS D162K substitution. In some embodiments, the KRAS mutant cancer comprises a KRAS amplification.

[0159] In some embodiments, the KRAS mutant cancer further comprises CCNE1 amplification. In some embodiments, a Next Generation Sequencing (NGS) panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, the KRAS mutant cancer further comprises cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion.

[0160] In some embodiments, the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer. In some embodiments, the KRAS mutant cancer is colorectal cancer. In some embodiments, the KRAS mutant cancer is non-small cell lung cancer (NSCLC). In some embodiments, the KRAS mutant cancer is pancreatic cancer. In some embodiments, the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor. In some embodiments, the method results in tumor necrosis.

[0161] In some embodiments, INX-315 is administered in a dosage form between about 100 mg and about 800 mg. In some embodiments, INX-315 is administered in a dosage form selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, INX-315 is administered at least once a day. In some embodiments, INX- 315 is continuously administered for at least 21 days, at least 24 days, at least 28 days, at least 35 days, or more than 35 days.

[0162] In some embodiments, the KRAS mutation is determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO / Reveal Dx Lung & Colon Cancer Assay (O / RDx-LCCA), therascreen KRAS RGQ PCR Kit, Praxis Extended RAS Panel, or a combination thereof.

[0163] In some embodiments, the method results in an improved lifespan for the patient as compared to the lifespan of a control patient that has not received a treatment with INX-315.

[0164] In some embodiments, the patient is a human.

[0165] INX-315 and CDK1 Inhibitor Combinations Effectively Treat CCNE1 Amplified Cancer

[0166] In one aspect, provided herein is a method for treating a patient having a CCNE1 amplified cancer, comprising administering to the patient an effective amount of INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor.

[0167] In an additional aspect, provided herein is a method for treating a patient having a CCNE1 amplified cancer, comprising: (i) obtaining a sample from the patient; (ii) detecting whether CCNE1 is amplified or overexpressed in the sample compared with a control sample; (iii) if CCNE1 is amplified or overexpressed, then administering to the patient: (a) an effective amount of INX-315, or a pharmaceutically acceptable salt thereof; and (b) an effective amount of a CDK1 inhibitor, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the CDK1 inhibitor is a CDKl-specific inhibitor. In some embodiments, the CDKl-specific inhibitor is selected from RO-3306, CGP-74514A, or BEY1107 (avotaciclib). In some embodiments, the CDKl-specific inhibitor is RO-3306. In some embodiments, the CDK1 inhibitor is a pan-CDK inhibitor. In some embodiments, the pan-CDK inhibitor is selected from alsterpaullone, kenpaullone, CVT-313, staurosporine, JNJ-7706621, olomoucine, SU9516, CDKi277, bohemine, CYC202, 3-ATA, NU2058, purvalanol A, BMS- 265246, flavopiridol (alvocidib), roniciclib (BAY1000394), P276-00 (riviciclib), dinaciclib (SCH727965), AT7519, seliciclib (roscovitine), AG-024322, PHA-793887, R547, RGB-286638, AZD-5438, indirubin (couroupitine B), milciclib, PHA-848125AC, or indirubin-5-sulfonic acid.

[0169] In an additional aspects, disclosed herein are methods for treating a patient with a cancer, comprising monitoring a sample of the patient for amplification of CCNE1 compared with a control sample, wherein, upon determining a patient has a cyclin E amplified cancer, administering to the patient an effective amount of INX-315, or a pharmaceutically acceptable salt thereof, in combination or alternation with a CDK1 inhibitor. In certain embodiments, CCNE1 is overexpressed and / or activated in a sample of a patient to be treated by at least 1.5-fold, at least 2.0-fold, at least 2.5-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, or greater than 5.0-fold compared with a control sample. In some embodiments, the CDK1 inhibitor is a CDKl-specific inhibitor selected from RO-3306, CGP-74514A, or BEY1107 (avotaciclib). In some embodiments, the CDK1 inhibitor is a pan CDK inhibitor selected from alsterpaullone, kenpaullone, CVT-313, staurosporine, JNJ-7706621, olomoucine, SU9516, CDKi277, bohemine, CYC202, 3-ATA, NU2058, purvalanol A, BMS-265246, flavopiridol (alvocidib), roniciclib (BAY1000394), P276-00 (riviciclib), dinaciclib (SCH727965), AT7519, seliciclib (roscovitine), AG-024322, PHA-793887, R547, RGB-286638, AZD-5438, indirubin (couroupitine B), milciclib, PHA-848125AC, or indirubin-5-sulfonic acid. In some embodiments, the CDK1 inhibitor is RO-3306. In some embodiments, an NGS panel test is used to confirm CCNE1 overexpression or amplification status. In some embodiments, an NGS panel test to confirm CCNE1 overexpression or amplification status is selected from Foundation One® CDx, Foundation One® Liquid CDx, Tempus xT (solid tumor), Tempus xF (liquid biopsy), Caris® Life Sciences Molecular Profiling, or OncoHelix Solid Tumor NGS. In some embodiments, the patient sample is selected from tumor tissue, formalin-fixed paraffin embedded (FFPE) tumor tissue, blood, or blood plasma.

[0170] In some embodiments, the CCNE1 amplified cancer is selected from ovarian cancer, uterine cancer, uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC), ovarian cancer, ovarian serous cystadenocarcinoma (OV), sarcoma (SARC), lung cancer, lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LU AD), stomach cancer, stomach adenocarcinoma (STAD), bladder cancer, bladder urothelial carcinoma (BLCA), esophageal cancer, esophageal carcinoma (ESCA), adrenocortical carcinoma, breast cancer, breast invasive carcinoma (BRCA), pancreatic cancer, pancreatic adenocarcinoma (PAAD), fallopian tube cancer, primary peritoneal cancer liver cancer, liver hepatocellular carcinoma (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), endocervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, skin cutaneous melanoma (SKCM), glioblastoma multiforme (GBM), kidney cancer, or kidney chromophobe (KICH). In some embodiments, the CCNE1 amplified cancer is an ovarian cancer. In some embodiments, the CCNE1 amplified cancer is CDK4 / 6 inhibitor-resistant. In certain embodiments, the cancer is advanced and / or metastatic cancer. In certain embodiments, the cancer is advanced unresectable cancer. In certain embodiments, the cancer is platinum-refractory and / or platinum -resistant. In certain embodiments, the cancer has progressed following a prior standard of care regimen. In certain embodiments, the cancer has progressed following a prior standard systemic therapy. In certain embodiments, the cancer has progressed following a prior systemic anti-cancer therapy. In certain embodiments, the cancer has progressed following a prior regimen comprising a platinum analog. In certain embodiments, the cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor. In some embodiments, the CCNE1 amplified cancer is uterine cancer. In some embodiments, the CCNE1 amplified cancer is ovarian cancer. In some embodiments, the CCNE1 amplified cancer is breast cancer. In some embodiments, the CCNE1 amplified cancer is prostate cancer. In some embodiments, the CCNE1 amplified cancer is bladder cancer. In some embodiments, the CCNE1 amplified cancer is a sarcoma. In certain embodiments, the TNX-315 and CDK1 combinations are useful for the treatment of an ovarian cancer which has an amplification of CCNE1. In certain embodiments, the ovarian cancer is an advanced and / or metastatic cancer. In certain embodiments, the ovarian cancer is advanced unresectable cancer. In certain embodiments, the ovarian cancer is platinum-refractory and / or platinum-resistant. In certain embodiments, the ovarian cancer has progressed following a prior standard of care regimen. In certain embodiments, the ovarian cancer has progressed following a prior standard systemic therapy. In certain embodiments, the ovarian cancer has progressed following a prior systemic anti-cancer therapy. In certain embodiments, the ovarian cancer has progressed following a prior regimen comprising a platinum analog. In certain embodiments, the ovarian cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor. In certain embodiments, the ovarian cancer has progressed following a prior regimen comprising an estrogen inhibitor.

[0171] In certain embodiments, the INX-315 and CDK1 inhibitor combination described herein is used to treat a cyclin E overexpressed or amplified non-small cell lung cancer (NSCLC). In certain embodiments, the NSCLC has an EGFR mutation. In certain embodiments, the NSCLC has an EGFR mutation and an EGFR inhibitor failed (e.g. 2nd line therapy). In certain embodiments, an ALK inhibitor failed (e.g. 2nd line therapy). In certain embodiments, the NSCLC has an KRAS mutation.

[0172] In certain embodiments, the INX-315 and CDK1 inhibitor combination described herein is used to treat a cyclin E overexpressed or amplified prostate cancer. In certain embodiments, the prostate cancer is castration resistant. In certain embodiments, a prior chemotherapeutic agent already failed (e.g. 2nd line therapy).

[0173] In certain embodiments, the INX-315 and CDK1 inhibitor combination described herein is used to treat a cyclin E overexpressed or amplified lymphoma. In certain embodiments, the lymphoma is mantel cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), or diffuse large B-cell lymphoma (DLBCL). In certain embodiments, a prior chemotherapeutic agent already failed (e g. 2nd line therapy). In certain embodiments, the TNX-315 and CDK1 inhibitor combination described herein is used to treat a cyclin E overexpressed or amplified melanoma. In certain embodiments, the melanoma has a BRAF mutation.

[0174] In certain embodiments, the INX-315 and CDK1 inhibitor combination described herein is used to treat a cyclin E overexpressed or amplified gastrointestinal stromal tumor (GIST). In certain embodiments, the treatment with imatinib or sunitinib already failed (e.g. 2nd line therapy).

[0175] In some embodiments, INX-315 is administered in a dosage form between about 100 mg and about 800 mg. In some embodiments, INX-315 is administered in a dosage form selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg. In some embodiments, INX-315 is administered at least once a day. In some embodiments, INX- 315 is continuously administered for at least 21 days, at least 24 days, at least 28 days, at least 35 days, or more than 35 days.

[0176] In some embodiments, the method results in an improved lifespan for the patient as compared to the lifespan of a control patient that has not received a treatment with INX-315.

[0177] In some embodiments, the patient is a human.

[0178] Genetic Tests for KRAS Mutation Status

[0179] In some aspects, the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt as described herein, is used as a medicament in therapeutic and / or prophylactic treatment of a patient having a KRAS mutation as determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO / Reveal Dx Lung & Colon Cancer Assay (O / RDx-LCCA), therascreen KRAS RGQ PCR Kit, Praxis Extended RAS Panel, or a combination thereof.

[0180] In one aspect, provided herein are compositions and methods of determining the KRAS mutation status in a patient and then administering a combination therapy comprising the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt as described herein, optionally in a pharmaceutical composition to said patient, wherein the composition and / or method delays acquired resistance to a RAS inhibitor in the patient. In some embodiments, INX-315 is administered in combination with a RAS inhibitor. In some embodiments, the RAS inhibitor is selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS- 3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS- 10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI- 2852, BI-2493, YL-15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof

[0181] Pharmaceutical Combinations and Dosage Forms

[0182] In one aspect, provided herein is a pharmaceutical combination comprising: (i) an effective amount of the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof; (ii) an effective amount of a RAS inhibitor selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI- 1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX-4933, RMC- 4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY-5933, BBO- 8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof; and (iii) one or more pharmaceutically acceptable excipients.

[0183] In some embodiments, the pharmaceutical combination comprises an amorphous spray - dried dispersion (ASD) of INX-315. In some embodiments, the ASD further comprises a precipitation preventer. In some embodiments, INX-315 is between about 20% and about 60% by weight of the ASD. In some embodiments, INX-315 is between about 30% and about 50% by weight of the ASD. In some embodiments, INX-315 is about 40% by weight of the ASD.

[0184] In some embodiments, the pharmaceutical combination in a dosage from selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg of INX-315, or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the precipitation preventer is selected from a cellulose derivative, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxy ethyl cellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethyl cellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, PVP K 30, PVP K 25, PVP VA64, or PVP VA37. In some embodiments, the precipitation preventer is HPMCAS-HG. In some embodiments, the precipitation preventer in the ASD is between about 40% and about 80% by weight of the ASD. In some embodiments, the precipitation preventer in the ASD is about 60% by weight of the ASD.

[0186] In some embodiments, the pharmaceutical combinations comprising an amorphous INX- 315 or a pharmaceutically acceptable salt thereof, and a precipitation preventer spray-dried together in an ASD formulation, are then tableted together with one or more additional therapeutic agents selected from a RAS inhibitor, a CDK4 / 6 inhibitor, or a combination thereof, and one or more pharmaceutically acceptable excipients selected from insoluble diluent, soluble diluent, disintegrant, glidant, and / or lubricant which are dry -granulated, dry-blended. Non-limiting examples of the one or more pharmaceutically acceptable excipients include vitamin E (for example, d-alpha-tocopheryl polyethylene glycol succinate), mannitol, cellulose (for example microcrystalline cellulose), croscarmellose sodium, silicon dioxide (for example untreated fumed colloidal), and sodium stearyl fumarate. In some embodiments, a pharmaceutical composition according to the present invention is formulated into a dosage unit form, such as an oral dosage unit form. In some embodiments, a pharmaceutical composition according to the present invention is formulated into a tablet dosage form. In some embodiments, the pharmaceutical combinations comprising amorphous INX-315, or a pharmaceutically acceptable salt thereof comprise one or more of the following pharmaceutically acceptable excipients:

[0187] In one aspect, provided herein is the use of the pharmaceutical composition in the manufacture of a medicament for delaying acquired resistance to a RAS inhibitor a patient having a KRAS mutant cancer.

[0188] In another aspect, provided herein is method for delaying acquired resistance to a RAS inhibitor a patient having a KRAS mutant cancer, comprising administering to the patient an effective amount of the pharmaceutical composition.

[0189] In some embodiments, the KRAS mutant cancer comprises KRAS mutant cancer.

[0190] In an alternative aspect, provided herein is a pharmaceutical combination comprising (i) an effective amount of INX-315, or a pharmaceutically acceptable salt thereof; (ii) an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor selected from RO-3306, CGP-74514A, BEY1107 (avotaciclib), alsterpaullone, kenpaullone, CVT-313, staurosporine, JNJ-7706621, olomoucine, SU9516, CDKi277, bohemine, CYC202, 3-ATA, NU2058, purvalanol A, BMS- 265246, flavopiridol (alvocidib), roniciclib (BAY1000394), P276-00 (riviciclib), dinaciclib (SCH727965), AT7519, seliciclib (roscovitine), AG-024322, PHA-793887, R547, RGB-286638, AZD-5438, indirubin (couroupitine B), milciclib, PHA-848125AC, or indirubin-5-sulfonic acid, or a pharmaceutically acceptable salt thereof; and (iii) one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical combination comprises an amorphous spray- dried dispersion (ASD) of INX-315. In some embodiments, INX-315 is between about 20% and about 60% by weight of the ASD. In some embodiments, INX-315 is between about 30% and about 50% by weight of the ASD. In some embodiments, INX-315 is about 40% by weight of the ASD. In some embodiments, the pharmaceutical combination is in a dosage from selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg of INX-315, or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the ASD further comprises a precipitation preventer. In some embodiments, the precipitation preventer is selected from a cellulose derivative, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxy ethyl cellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethyl cellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, PVP K 30, PVP K 25, PVP VA64, or PVP VA37. In some embodiments, the precipitation preventer is HPMCAS-HG. In some embodiments, the precipitation preventer in the ASD is between about 40% and about 80% by weight of the ASD. In some embodiments, the precipitation preventer in the ASD is about 60% by weight of the ASD.

[0192] In one aspect, provided herein is the use of an effective amount of a pharmaceutical combination comprising INX-315, or a pharmaceutically acceptable salt thereof, and a CDK1 inhibitor, in the manufacture of a medicament for treating a patient having a CCNE1 amplified cancer.

[0193] In yet another aspect, provided herein is a method for treating a patient having a CCNE1 amplified cancer, comprising administering to the patient an effective amount of the pharmaceutical combination comprising INX-315, or a pharmaceutically acceptable salt thereof, and a CDK1 inhibitor.

[0194] INX-315 or its pharmaceutically acceptable salt can be administered in an effective amount according to the methods described herein to a host to treat any of the disorders described herein using any suitable approach which achieves the desired therapeutic result. The amount and timing of INX-315 administration will, of course, be dependent on the host being treated, the instructions of the supervising medical specialist, on the time course of the exposure, on the manner of administration, on the pharmacokinetic properties, and on the judgment of the prescribing physician. Thus, because of host-to-host variability, the dosages given below are a guideline and the physician can titrate doses of the compound to achieve the treatment that the physician considers appropriate for the host. In considering the degree of treatment desired, the physician can balance a variety of factors such as age and weight of the host, presence of preexisting disease, as well as presence of other diseases.

[0195] The therapeutically effective dosage of INX-315 or a pharmaceutically acceptable salt thereof can be determined by the health care practitioner depending on the condition, size and age of the patient as well as the route of delivery. In certain non-limited embodiments, a dosage from about 0.1 to about 200 mg / kg has therapeutic efficacy, with all weights being calculated based upon the weight of the INX-315, including the cases where a salt is employed. In some embodiments, the dosage is about or greater than 0.1, 0.5, 1, 5, 10, or 25 mg / kg.

[0196] In some embodiments, the pharmaceutical combination is in a dosage form that contains from about 50 to 500 mg, for example from 100 to 400 or 500 mg, or further for example, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg of INX-315 in a unit dosage form. In some embodiments, the pharmaceutical combination is in a dosage form that contains about 100 mg or 150 mg of INX-315, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is in a dosage form that contains about 200 mg of INX-315, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is in a dosage form that contains about 300 mg of INX-315, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is in a dosage form that contains about 400 mg of INX-315, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is in a dosage form that contains about 500 mg of INX-315, or a pharmaceutically acceptable salt thereof. The pharmaceutical combination may also include a molar ratio of the INX-315 or a pharmaceutically acceptable salt thereof and an additional active agent (such as a selective CDK 4 inhibitor), in a ratio that achieves the desired results. In some embodiments, TNX-315 or a pharmaceutically acceptable salt thereof is administered once-a-day (QD). In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered twice a day (QD). In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered at least once-a-day for at least 21 days, at least 24 days, at least 28 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 180 days, at least 1 year or longer, including indefinitely, or until the healthcare provider decides that the drug is no longer necessary.

[0197] In accordance with the presently disclosed methods, an oral administration can be in any desired form such as a solid, gel or liquid, including a solution, suspension, or emulsion. In some embodiments, the INX-315 or salt thereof is administered by inhalation or intramuscularly as a liposomal suspension. When administered through inhalation INX-315 or salt may be in the form of a plurality of solid particles or droplets having any desired particle size, and for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more microns, and optionally from about 1 to about 2 microns.

[0198] The pharmaceutical formulations can comprise INX-315 or a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier. If a solution is desired, water may sometimes be the carrier of choice for water-soluble compounds or salts. With respect to the water- soluble compounds or salts, an organic vehicle, such as glycerol, propylene glycol, polyethylene glycol, or mixtures thereof, can be suitable. In the latter instance, the organic vehicle can contain a substantial amount of water. The solution in either instance can then be sterilized in a suitable manner known to those in the art, and for illustration by filtration through a 0.22-micron filter.

[0199] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the INX-315 is sufficient to provide a practical quantity of material for administration per unit dose of INX-315.

[0200] Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical combination, which do not substantially interfere with the activity of INX-315.

[0201] Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles. A biological buffer can be any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like.

[0202] Depending on the intended mode of administration, the pharmaceutical combinations can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include an effective amount of INX-315 in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.

[0203] Thus, the compositions of the disclosure can be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intrathecal, and subcutaneous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.

[0204] For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, INX-315 or a pharmaceutically acceptable salt thereof and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical combination to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods of preparing such dosage forms are known, or can be apparent, to those skilled in this art; for example, see Remington ’s Pharmaceutical Sciences, 23rd Edition, A. Adejare, Editor, Academic Press (2020); Handbook of Pharmaceutical Excipients, 6th Edition, R. C. Rowe, P. J. Sheskey, M. E. Quinn Editors, American Pharmaceutical Association, and Pharmaceutical Press (2009); and Handbook of Pharmaceutical Additives, 3rd Edition, compiled by Michael and Irene Ash, Synapse Information Resources (2007).

[0205] In yet another embodiment is the use of permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

[0206] For oral administration, the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. Typically, the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. When liquid suspensions are used, the INX-315 can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and / or sweetening agents can be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.

[0207] Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions. Preferably, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained. Parenteral administration includes intraarticular, intramuscular, intradermal, intraperitoneal, and subcutaneous routes. Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. A formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.

[0208] In addition to INX-315 or a pharmaceutically acceptable salt thereof, the pharmaceutical formulations can contain other additives, such as pH-adjusting additives. In particular, useful pH- adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Further, the formulations can contain antimicrobial preservatives. Useful antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. An antimicrobial preservative is typically employed when the formulations is placed in a vial designed for multi-dose use. The pharmaceutical formulations described herein can be lyophilized using techniques well known in the art. In some embodiments, INX-315 or its pharmaceutically acceptable salt can be provided in the form of a lyophilizate, which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form liquid formulation suitable for injection thereof into a host. When INX- 315 or a pharmaceutically acceptable salt thereof is substantially water-insoluble, a sufficient amount of emulsifying agent, which is physiologically acceptable, can be employed in sufficient quantity to emulsify INX-315 or the pharmaceutically acceptable salt thereof in an aqueous carrier. Particularly useful emulsifying agents include phosphatidyl cholines and lecithin.

[0209] Pharmaceutical formulations also are provided which provide a controlled release of INX- 315 or a pharmaceutically acceptable salt thereof described herein, including through the use of a degradable polymer, as known in the art.

[0210] The term "pharmaceutically acceptable salts" as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with hosts (e g., human hosts) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of INX-315 as described herein.

[0211] Thus, the term "salts" refers to the relatively non -toxic, inorganic and organic acid addition salt of INX-315. These salts can be prepared during the final isolation and purification of the compound or by separately reacting the purified INX-315 in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Basic compounds are capable of forming a wide variety of different salts with various inorganic and organic acids. Acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms may differ from their respective salt forms in certain physical properties such as solubility in polar solvents.

[0212] Salts can be prepared from inorganic acids include hydrochloric, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like. Representative salts include the hydrobromide, hydrochloride, sulfate, hemisulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.

[0213] Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.

[0214] Preferably, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media. In addition, parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.

[0215] Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.

[0216] Sterile injectable solutions are prepared by incorporating INX-315 of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

[0217] Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing INX-315 or a pharmaceutically acceptable salt thereof with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0218] Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.

[0219] Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. In some embodiments, microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.

[0220] Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single / -multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung.

[0221] CDK2 in the Cell Cycle

[0222] Cell division is regulated by the cell cycle, which is divided into four phases: G1 phase (cell growth and machinery synthesis), S phase (DNA replication to generate two identical sets of chromosomes), G2 phase (cell growth and supplemental machinery synthesis), and M phase (single cell divides into two identical daughter cells). The progression between cell cycle phases is primarily governed by cyclins and cyclin-dependent kinases (CDKs) (Asghar et al. Nat Rev Drug Discov. 14(2): 130-46(2015)), which are activated or inhibited in response to a complex system of cell signaling networks that interpret extracellular signals.

[0223] Cyclin dependent kinase 2 (CDK2), which is activated following binding with cyclin E, is required to enter S-phase in the cell cycle (Merrick, K.A. et al. Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation. Mol Cell. 42:624-636(2011)). The CDK2 / cyclin E protein complex, as well as the CDK4 / 6 / cyclin D protein complex, phosphorylates retinoblastoma (Rb), releasing the G1 transcription factor E2F to promote S-phase completion (Sherr, C.J. Mammalian G1 cyclins. Cell. 73(6): 1059-65(1993 Jun 18); Asghar et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 14(2): 130-146(2015). The CDK2 / cyclin E protein complex, in addition to regulating the Gl / S transition, mediates histone biosynthesis and centrosome duplication (Matsumoto, Y.K. et al. CDK2 is required for centrosome duplication in mammalian cells. Curr Biol. 9:429-432(1999); Nelson, D.M. et al. Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin / cdk2 activity. Mol Cell Biol. 22(21):7459-7472(2002 Nov).

[0224] CDK2 -mediated hyperphosphorylation leads to complete inactivation of the Rb protein, which is necessary to promote S-phase completion. Thus, retinoblastoma is considered a key protein in the cell cycle system that includes the CDK2 / cyclin E protein complex. Evidence suggests that CDK2 fundamentally regulates cellular proliferation and CDK4 / 6 inhibitor resistance mechanisms, highlighting the potential for targeting CDK2 in cancer (Tadesse, S. et al. Cyclin- Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update. J Med Chem. 62(9):4233- 4251(2019 May 9)).

[0225] KRAS and KRAS-mutant associated disorders

[0226] The most commonly mutated gene in human cancer is KRAS, with mutant forms present in approximately 25% of all tumors and in over 200,000 new cancer patients per year in the United States. KRAS mutations cause unrestricted activation of the RAF-MEK-ERK and PI3K-AKT pathways.

[0227] The protein KRAS is a membrane-associated GTPase that converts GTP into GDP, acting as a molecular switch to control cellular differentiation, growth, and survival. The KRAS protein is turned on (activated) by binding to GTP to effect cellular signaling. The KRAS protein is turned off (inactivated) when the GTP is converted into GDP. The KRAS protein, when bound to GDP, does not transmit cellular signaling.

[0228] Missense mutations within KRAS and dysregulated KRAS isoform expression are thought to be core drivers of cancer. The codons encoding amino acid positions G12, G13, and Q61 are commonly altered by missense mutation, such that the amino acids at these residues are substituted for different amino acids. KRAS mutations of the G12, G13, and Q61 codons are the dominant mutations in cancer. In addition, alternative splicing of KRAS encodes the highly similar KRAS4A and KRAS4B isoforms. These isoforms function divergently, however, when expressed in different tissue types. Sequence variation between isoforms in the C-terminal hyper-variable regions likely contributes to this functional divergence. For clinical and research purposes, KRAS is commonly referred to as the KRAS4B isoform, which is the gene product most commonly expressed in human cells (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15: 152(2022)).

[0229] An estimated 240,000 new patients per year each harbor a KRAS mutation, with mutant KRAS found in approximately 40% of colorectal cancers, 32% of lung cancers, and at least 90% of cases of pancreatic cancer (see Table 2 below). In fact, KRAS is mutated in approximately 14% of all human cancers (Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 23(6):703-713(2017 Jun)). Table 1. KRAS mutation incidence in KRAS-associated disorders1. ’Reproduced herein from Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15: 152(2022).

[0230] The most frequently altered codon in cancer is KRAS G12, accounting for 80% of all KRAS mutations (Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 23(6):703-713(2017 Jun)). An estimated 29,200 new patients per year in the United States each harbor a KRAS G12C substitution. The mutation causing KRAS G12C substitution is the most common KRAS mutation found in non-small cell lung cancer (NSCLC) (Table 1). Of the major clinically-recognized mutations, G12C is currently the only KRAS substitution targeted by FDA-approved drugs (sotorasib (Lumakras®), adagrasib (Krazati®)), indicated for locally advanced or metastatic NSCLC. These FDA-approved KRAS G12C inhibitors are also undergoing clinical studies in numerous countries for the treatment of solid tumors, colon cancer, colorectal cancer, lung cancer, melanoma, and pancreatic cancer.

[0231] An estimated 71 ,200 new patients per year in the United States each harbor a KRAS G12D mutation. The KRAS G12D substitution, for example, is the most common KRAS mutation found in pancreatic adenocarcinoma (Table 1).

[0232] An estimated 55,100 new patients per year in the United States each harbor a KRAS G12V mutation. The KRAS G12V substitution, for example, is the second most common KRAS mutation found in pancreatic adenocarcinoma (Table 1).

[0233] Pancreatic Cancer

[0234] Mutation of the KRAS gene is an integral event in the etiology of pancreatic cancer. For example, KRAS mutation occurs in 90% of all pancreatic adenocarcinoma patients (Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 23(6):703 -713(2017 Jun)). With a 5-year survival rate of 8%, pancreatic cancer is the deadliest cancer in the United States (Siegel, R.L. et al. Cancer statistics. CA Cancer J Clin. 66:7-30(2016)).

[0235] Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death among cancer patients in the United States and is one of the major causes of morbidity and mortality worldwide (Siegel, R.L. et al. Cancer statistics. CA Cancer J Clin. 66:7- 30(2016)). Standard of care for PDAC is surgery followed by adjuvant therapy. Only 15-20% of patients, however, eventually are eligible for surgery (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 8(9):a031435(2018 Sep)). Mutation of KRAS is a hallmark of PDAC, occurring in greater than 90% of all PDAC patients (Id.) (Table 1). The central role of KRAS in PDAC is supported by in vitro PDAC cancer cell models, in which RNA interference (RNAi) knockdown of KRAS demonstrates reduced cellular proliferation and induction of apoptosis (Collisson, E.A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 17(4):500-503(2011 Apr)). Furthermore, KRAS deletion in PDAC models using CRISPR / Cas-mediated genome editing significantly reduced in vitro proliferation and in vivo tumorigenic growth, which supports the rationale for targeting KRAS for the treatment of PDAC ((Muzumdar, M.D. et al. Survival of pancreatic cancer cells lacking KRAS function. Nat. Commun. 8(1): 1090(2017)). The development of PDAC is categorized as a step-wise progression which lasts approximately 12 years (lacobuzio-Donahue, C.A. et al. Genetic basis of pancreas cancer development and progression: Insights from whole-exome and whole-genome sequencing. Clin Cancer Res. 18:4257-4265(2012)). PDAC is typically characterized by histologically defined lesions with increasingly disrupted cellular morphology, dysplastic growth, and nuclear atypia (Cox, A.D. & Der, C.J. Ras history: The saga continues. Small GTPases. l(l):2-27(2010 Jul)). An early, initiating event in PDAC etiology is the development of activating KRAS mutations that trigger the transformation of normal pancreatic duct epithelium into pancreatic intraepithelial neoplasms (PanINs). Although relatively infrequent in other forms of cancer, KRAS G12R mutations comprise 16% of all KRAS mutations in PDAC (Waters, A.M. & Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 8(9):a031435(2018 Sep)).

[0236] Colorectal Cancer

[0237] One of the most common cancers worldwide is colorectal cancer (Porru, M. et al. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res. 37(l):57(2018 Mar 13), with most colorectal cancers being adenocarcinomas. KRAS is mutated in between about 27.9% to about 43.7% of all colorectal adenocarcinomas (Table 1). The current standard of care in colorectal cancer is a combination of chemotherapeutic agents, for example the protracted infusion of 5 -fluorouracil (5-FU) modulated by leucovorin in combination with irinotecan (FOLFIRI) or with oxaliplatin (FOLFOX), capecitabine and oxaliplatin combination (XELOX), or 5-FU, leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) (Id.). Lung Cancer

[0238] The most common form of cancer is lung cancer, which is responsible for the most cancer- related deaths worldwide (Westcott, P.M.K. & To, M.D. The genetics and biology of KRAS in lung cancer. Chin J Cancer. 32(2):63-70(2013 Feb)). The most common risk factor for lung cancer is smoking, with an estimated 80% of all lung cancer patients having previously smoked (Id.). KRAS is more frequently mutated in smokers compared to non-smokers, with the KRAS G12C mutation being the most common KRAS mutation in smokers with lung cancer (44%), followed by the mutation causing G12V substitution (19%) (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15: 152(2022)). In comparison, the KRAS G12D mutation is the most frequent KRAS mutation (56%) in non-smokers with lung cancer (Id.).

[0239] VCIQKRAS gene is mutated in 23% of all NSCLC (Table 1), with the KRAS G12C mutation comprising a 41% majority of all KRAS mutations in this population (Table 1) (Parikh, K. et al. Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol. 15: 152(2022)). KRAS mutations mostly occur in lung adenocarcinomas, the most common histological subclass of NSCLC. The KRAS G12C mutation is also the major KRAS mutation in lung adenocarcinoma, comprising approximately 43% of all KRAS mutations in this population (Waters, A.M. & Der, C J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 8(9):a031435(2018 Sep)). In other forms of NSCLC, however, the frequency of KRAS mutation is lower. For example, in squamous cell carcinoma (another subclass of NSCLC), KRAS mutations comprise 5% of all cases (Table 1) (Id.). In some embodiments, the NSCLC comprises lung adenocarcinoma or squamous cell carcinoma.

[0240] EMBODIMENTS

[0241] 1. A method for treating a patient having a KRAS mutant cancer, comprising administering to the patient an effective amount of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure: or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor.

[0242] 2. The method of embodiment 1, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

[0243] 3. The method of embodiment 1 or 2, wherein the CDK4 / 6 inhibitor is palbociclib.

[0244] 4. The method of any one of embodiments 1-3, wherein the KRAS mutant cancer comprises a mutation encoding a KRAS substitution.

[0245] 5. The method of embodiment 4, wherein the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution.

[0246] 6. The method of embodiment 4 or 5, wherein the KRAS substitution is a KRAS G12 substitution.

[0247] 7. The method of embodiment 5 or 6, wherein the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V. 8. The method of any one of embodiments 5-7, wherein the KRAS G12 substitution is a KRAS G12C substitution.

[0248] 9. The method of any one of embodiments 5-7, wherein the KRAS G12 substitution is a KRAS G12D substitution.

[0249] 10. The method of any one of embodiments 5-7, wherein the KRAS G12 substitution is a KRAS G12S substitution.

[0250] 11. The method of embodiment 5 or 6, wherein the KRAS substitution is a KRAS G13 substitution.

[0251] 12. The method of embodiment 5 or 6, wherein the KRAS substitution is a KRAS Q61 substitution.

[0252] 13. The method of embodiment 12, wherein the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R.

[0253] 14. The method of embodiment 5 or 6, wherein the KRAS substitution is a KRAS D162 substitution.

[0254] 15. The method of embodiment 14, wherein the KRAS D162 substitution is a KRAS D162K substitution.

[0255] 16. The method of any one of embodiments 1-3, wherein the KRAS mutant cancer comprises a KRAS amplification.

[0256] 17. The method of any one of embodiments 1-16, wherein the KRAS mutant cancer comprises loss of function of p53.

[0257] 18. The method of any one of embodiments 1-17, wherein the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer. 19. The method of any one of embodiments 1-17, wherein the KRAS mutant cancer is colorectal cancer.

[0258] 20. The method of any one of embodiments 1-17, wherein the KRAS mutant cancer is nonsmall cell lung cancer (NSCLC).

[0259] 21. The method of any one of embodiments 1-17, wherein the KRAS mutant cancer is pancreatic cancer.

[0260] 22. The method of any one of embodiments 1-21, wherein the KRAS mutant cancer has progressed following a prior regimen comprising a RAS inhibitor.

[0261] 23. The method of any one of embodiments 1-22, wherein the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

[0262] 24. A method for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof, wherein the patient has already received, will receive administration of, or is receiving the RAS inhibitor.

[0263] 25. The method of embodiment 24, further comprising administering to the patient an effective amount of a RAS inhibitor.

[0264] 26. The method of embodiment 24 or 25, wherein the RAS inhibitor is a KRAS inhibitor.

[0265] 27. The method of embodiment 26, wherein the KRAS inhibitor binds to or is selective for KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G12R. 28. The method of embodiment 26, wherein the KRAS inhibitor binds to or is selective for KRAS Q61H, KRAS Q61R, KRAS Q61L, KRAS Q61K, KRAS Q61P, or KRAS Q61E.

[0266] 29. The method of embodiment 26, wherein the KRAS inhibitor is a pan-KRAS inhibitor.

[0267] 30. The method of embodiment 20, wherein the KRAS inhibitor is an inhibitor of GDP -bound KRAS.

[0268] 31. The method of embodiment 30, wherein the GDP -bound KRAS inhibitor is selected from RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, BI-0474, or BI-2865.

[0269] 32. The method of embodiment 26, wherein the KRAS inhibitor is selected from or a pharmaceutically acceptable salt thereof.

[0270] 33. The method of embodiment 24 or 25, wherein the RAS inhibitor is selected from AMG- 510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ- 74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D- 1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC- 3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof. 34. The method of embodiment 33, wherein the RAS inhibitor is MRTX-1133

[0271] 35. The method of embodiment 33, wherein the RAS inhibitor is RMC-6236.

[0272] 36. The method of any one of embodiments 24-35, wherein the patient has a KRAS mutant cancer.

[0273] 37. The method of embodiment 36, wherein the KRAS mutant cancer comprises a mutation encoding a KRAS substitution.

[0274] 38. The method of embodiment 37, wherein the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution.

[0275] 39. The method of embodiment 37 or 38, wherein the KRAS substitution is a KRAS G12 substitution.

[0276] 40. The method of embodiment 38 or 39, wherein the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V.

[0277] 41. The method of any one of embodiments 38-40, wherein the KRAS G12 substitution is a KRAS G12C substitution.

[0278] 42. The method of any one of embodiments 38-40, wherein the KRAS G12 substitution is a KRAS G12D substitution.

[0279] 43. The method of any one of embodiments 38-40, wherein the KRAS G12 substitution is a KRAS G12S substitution.

[0280] 44. The method of embodiment 37 or 38, wherein the KRAS substitution is a KRAS G13 substitution.

[0281] 45. The method of embodiment 37 or 38, wherein the KRAS substitution is a KRAS Q61 substitution.

[0282] 46. The method of embodiment 45, wherein the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. 47. The method of embodiment 37 or 38, wherein the KRAS substitution is a KRAS DI 62 substitution.

[0283] 48. The method of embodiment 47, wherein the KRAS D162 substitution is a KRAS D162K substitution.

[0284] 49. The method of embodiment 36, wherein the KRAS mutant cancer comprises a KRAS amplification.

[0285] 50. The method of any one of embodiments 36-49, wherein the KRAS mutant cancer further comprises cyclin El (CCNE1) overexpression or amplification.

[0286] 51. The method of any one of embodiments 36-50, wherein the KRAS mutant cancer comprises loss of function of p53.

[0287] 52. The method of any one of embodiments 36-51, wherein the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer.

[0288] 53. The method of embodiments 36-51, wherein the KRAS mutant cancer is colorectal cancer.

[0289] 54. The method of any one of embodiments 36-51, wherein the KRAS mutant cancer is non- small cell lung cancer (NSCLC).

[0290] 55. The method of any one of embodiments 36-51, wherein the KRAS mutant cancer is pancreatic cancer.

[0291] 56. The method of any one of embodiments 36-55, wherein the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

[0292] 57. A method for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of a CDK2 inhibitor compound of structure:

[0293] or a pharmaceutically acceptable salt thereof, wherein the patient has already received or is receiving the RAS inhibitor.

[0294] 58. The method of embodiment 57, further comprising administering to the patient an effective amount of a RAS inhibitor.

[0295] 59. The method of embodiment 57 or 58, wherein the RAS inhibitor is a KRAS inhibitor.

[0296] 60. The method of embodiment 59, wherein the KRAS inhibitor binds to or is selective for KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G12R.

[0297] 61. The method of embodiment 59, wherein the KRAS inhibitor binds to or is selective for KRAS Q61H, KRAS Q61R, KRAS Q61L, KRAS Q61K, KRAS Q61P, or KRAS Q61E.

[0298] 62. The method of embodiment 59, wherein the KRAS inhibitor is a pan-KRAS inhibitor.

[0299] 63. The method of embodiment 59, wherein the KRAS inhibitor is an inhibitor of GDP -bound KRAS.

[0300] 64. The method of embodiment 63, wherein the GDP -bound KRAS inhibitor is selected from RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, BI-0474, or BI-2865.

[0301] 65. The method of embodiment 59, wherein the KRAS inhibitor is selected from or a pharmaceutically acceptable salt thereof.

[0302] 66. The method of embodiment 58, wherein the RAS inhibitor is selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D- 1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC- 3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof.

[0303] 67. The method of embodiment 66, wherein the RAS inhibitor is MRTX-1133

[0304] 68. The method of embodiment 66, wherein the RAS inhibitor is RMC-6236.

[0305] 69. The method of any one of embodiments 57-68, wherein the KRAS mutant cancer comprises a mutation encoding a KRAS substitution.

[0306] 70. The method of embodiment 69, wherein the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution. 71. The method of embodiment 69 or 70, wherein the KRAS substitution is a KRAS G12 substitution.

[0307] 72. The method of embodiment 70 or 71, wherein the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V.

[0308] 73. The method of any one of embodiments 70-72, wherein the KRAS G12 substitution is a KRAS G12C substitution.

[0309] 74. The method of any one of embodiments 70-72, wherein the KRAS G12 substitution is a KRAS G12D substitution.

[0310] 75. The method of any one of embodiments 70-72, wherein the KRAS G12 substitution is a KRAS G12S substitution.

[0311] 76. The method of embodiment 69 or 70, wherein the KRAS substitution is a KRAS G13 substitution.

[0312] 77. The method of embodiment 69 or 70, wherein the KRAS substitution is a KRAS Q61 substitution.

[0313] 78. The method of embodiment 77, wherein the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R.

[0314] 79. The method of embodiment 69 or 70, wherein the KRAS substitution is a KRAS DI 62 substitution.

[0315] 80. The method of embodiment 79, wherein the KRAS DI 62 substitution is a KRAS D162K substitution.

[0316] 81. The method of any one of embodiments 57-68, wherein the KRAS mutant cancer comprises a KRAS amplification.

[0317] 82. The method of any one of embodiments 57-81, wherein the KRAS mutant cancer further comprises cyclin El (CCNE1) overexpression or amplification.

[0318] 83. The method of any one of embodiments 57-82, wherein the KRAS mutant cancer comprises loss of function of p53. 84. The method of any one of embodiments 57-83, wherein the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LUAD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer.

[0319] 85. The method of any one of embodiments 57-83, wherein the KRAS mutant cancer is colorectal cancer.

[0320] 86. The method of any one of embodiments 57-83, wherein the KRAS mutant cancer is non- small cell lung cancer (NSCLC).

[0321] 87. The method of any one of embodiments 57-83, wherein the KRAS mutant cancer is pancreatic cancer.

[0322] 88. The method of any one of embodiments 57-87, wherein the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

[0323] 89. A method for treating a patient having a KRAS mutant cancer, comprising:

[0324] (i) obtaining a sample from the patient;

[0325] (ii) detecting whether KRAS is mutated in the sample compared with a control sample;

[0326] (iii) if KRAS comprises a mutation, then administering to the patient:

[0327] (a) an effective amount of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof; and (b) an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0328] 90. A method for treating a patient having a KRAS mutant cancer comprising loss of function of p53, comprising administering to the patient an effective amount of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof.

[0329] 91. A method for treating a patient having a KRAS mutant cancer with a p53 loss of function mutation, comprising: (i) obtaining a sample from the patient;

[0330] (ii) detecting whether the sample has a p53 loss of function mutation compared with a control sample;

[0331] (iii) if the sample comprises a p53 loss of function mutation, then administering to the patient: (a) an effective amount of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof.

[0332] 92. The method of embodiment 90 or 91, further comprising administering to the patient an effective amount of a RAS inhibitor.

[0333] 93. The method of embodiment 92, wherein the RAS inhibitor is a KRAS inhibitor.

[0334] 94. The method of embodiment 93, wherein the KRAS inhibitor binds to or is selective for KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G12R.

[0335] 95. The method of embodiment 93, wherein the KRAS inhibitor binds to or is selective for KRAS Q61H, KRAS Q61R, KRAS Q61L, KRAS Q61K, KRAS Q61P, or KRAS Q61E.

[0336] 96. The method of embodiment 93, wherein the KRAS inhibitor is a pan-KRAS inhibitor.

[0337] 97. The method of embodiment 93, wherein the KRAS inhibitor is an inhibitor of GDP -bound KRAS.

[0338] 98. The method of embodiment 97, wherein the GDP -bound KRAS inhibitor is selected from RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, BI-0474, or BI-2865.

[0339] 99. The method of embodiment 92 or 93, wherein the RAS inhibitor is selected from AMG- 510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ- 74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D- 1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC- 3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or Bl-2865, or a pharmaceutically acceptable salt thereof.

[0340] 100. The method of any one of embodiments 1-99, wherein the KRAS mutation is determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO / Reveal Dx Lung & Colon Cancer Assay (O / RDx-LCCA), therascreen KRAS RGQ PCRKit, Praxis Extended RAS Panel, or a combination thereof.

[0341] 101. A method for treating a patient having a CCNE1 amplified cancer, comprising administering to the patient an effective amount of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure: or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor. 102. A method for treating a patient having a CCNE1 amplified cancer, comprising:

[0342] (i) obtaining a sample from the patient;

[0343] (ii) detecting whether CCNE1 is amplified or overexpressed in the sample compared with a control sample;

[0344] (iii) if CCNE1 is amplified or overexpressed, then administering to the patient: (a) an effective amount of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof; and

[0345] (b) an effective amount of a CDK1 inhibitor, or a pharmaceutically acceptable salt thereof.

[0346] 103. The method of embodiment 101 or 102, wherein the CDK1 inhibitor is a CDKl-specific inhibitor.

[0347] 104. The method of embodiment 103, wherein the CDKl-specific inhibitor is selected from RO- 3306, CGP-74514A, or BEY1107 (avotaciclib).

[0348] 105. The method of 103 or 104, wherein the CDKl-specific inhibitor is RO-3306.

[0349] 106. The method of embodiment 102, wherein the CDK1 inhibitor is a pan-CDK inhibitor.

[0350] 107. The method of embodiment 106, wherein the pan-CDK inhibitor is selected from alsterpaullone, kenpaullone, CVT-313, staurosporine, JNJ-7706621, olomoucine, SU9516, CDKi277, bohemine, CYC202, 3 -ATA, NU2058, purvalanol A, BMS-265246, flavopiridol (alvocidib), roniciclib (BAY1000394), P276-00 (riviciclib), dinaciclib (SCH727965), AT7519, seliciclib (roscovitine), AG-024322, PHA-793887, R547, RGB-286638, AZD-5438, indirubin (couroupitine B), milciclib, PHA-848125AC, or indirubin-5-sulfonic acid.

[0351] 108. The method of any one of embodiments 101-107, wherein the CCNE1 amplified cancer is selected from ovarian cancer, uterine cancer, uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC), ovarian cancer, ovarian serous cystadenocarcinoma (OV), sarcoma (SARC), lung cancer, lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), stomach cancer, stomach adenocarcinoma (STAD), bladder cancer, bladder urothelial carcinoma (BLCA), esophageal cancer, esophageal carcinoma (ESCA), adrenocortical carcinoma, breast cancer, breast invasive carcinoma (BRCA), pancreatic cancer, pancreatic adenocarcinoma (PAAD), fallopian tube cancer, primary peritoneal cancer liver cancer, liver hepatocellular carcinoma (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), endocervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, skin cutaneous melanoma (SKCM), glioblastoma multiforme (GBM), kidney cancer, or kidney chromophobe (KICH). 109. The method of any one of embodiments 101-107, wherein the CCNE1 amplified cancer is non-small cell lung cancer (NSCLC).

[0352] 110. The method of any one of embodiments 101-107, wherein the CCNE1 amplified cancer is ovarian cancer.

[0353] 111. The method of any one of embodiments 101-107, wherein the CCNE1 amplified cancer is breast cancer.

[0354] 112. The method of any one of embodiments 101-111, wherein an NGS panel test is used to confirm CCNE1 overexpression or amplification status, and wherein the NGS panel test is selected from Foundation One® CDx, Foundation One® Liquid CDx, Tempus xT (solid tumor), Tempus xF (liquid biopsy), Caris® Life Sciences Molecular Profiling, or OncoHelix Solid Tumor NGS.

[0355] 113. The method of any one of embodiments 1-112, wherein the method results in tumor necrosis.

[0356] 114. The method of any one of embodiments 1-113, wherein INX-315 is administered in a dosage form between about 100 mg and about 800 mg.

[0357] 115. The method of any one of embodiments 1-114, wherein INX-315 is administered in a dosage form selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg.

[0358] 116. The method of any one of embodiments 1-115, wherein INX-315 is administered at least once a day.

[0359] 117. The method of any one of embodiments 1-116, wherein INX-315 is continuously administered for at least 21 days, at least 24 days, at least 28 days, at least 35 days, or more than 35 days.

[0360] 118. The method of any one of embodiments 1-117, wherein the patient is a human.

[0361] 119. A pharmaceutical combination comprising:

[0362] (i) an effective amount of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:

[0363] or a pharmaceutically acceptable salt thereof;

[0364] (ii) an effective amount of a KRAS inhibitor selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853,

[0365] ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-

[0366] 1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBL351 (GFH925) BI- 1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX- 4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY- 5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof; and

[0367] (iii) one or more pharmaceutically acceptable excipients.

[0368] 120. The pharmaceutical combination of embodiment 119, comprising an amorphous spray- dried dispersion (ASD) of INX-315.

[0369] 121. The pharmaceutical combination of embodiment 120, wherein INX-315 is between about 20% and about 60% by weight of the ASD.

[0370] 122. The pharmaceutical combination of embodiment 120 or 121, wherein INX-315 is between about 30% and about 50% by weight of the ASD. 123. The pharmaceutical combination of embodiments 120-122, wherein INX-315 is about 40% by weight of the ASD.

[0371] 124. The pharmaceutical combination of any one of embodiments 119-123, in a dosage from selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg of INX-315, or a pharmaceutically acceptable salt thereof.

[0372] 125. The pharmaceutical combination of any one of embodiments 120-124, wherein the ASD further comprises a precipitation preventer.

[0373] 126. The pharmaceutical combination of embodiment 125, wherein the precipitation preventer is selected from a cellulose derivative, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxy ethyl cellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethyl cellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, PVP K 30, PVP K 25, PVP VA64, or PVP VA37.

[0374] 127. The pharmaceutical combination of embodiment 125 or 126, wherein the precipitation preventer is HPMCAS-HG.

[0375] 128. The pharmaceutical combination of any one of embodiments 125-127, wherein the precipitation preventer in the ASD is between about 40% and about 80% by weight of the ASD.

[0376] 129. The pharmaceutical combination of any one of embodiments 125-128, wherein the precipitation preventer in the ASD is about 60% by weight of the ASD.

[0377] 130. Use of an effective amount of the pharmaceutical combination of any one of embodiments 119-129, in the manufacture of a medicament for delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer. 131. A method for delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer, comprising administering to the patient an effective amount of the pharmaceutical combination of any one of embodiments 119-129.

[0378] 132. Use of an effective amount of the pharmaceutical combination of any one of embodiments 119-129, in the manufacture of a medicament for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof.

[0379] 133. A method for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical combination of any one of embodiments 119-129.

[0380] 134. A pharmaceutical combination comprising:

[0381] (i) an effective amount of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure: or a pharmaceutically acceptable salt thereof;

[0382] (ii) an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor selected from RO-3306, CGP-74514A, BEY1107 (avotaciclib), alsterpaullone, kenpaullone, CVT-313, staurosporine, JNJ-7706621, olomoucine, SU9516, CDKi277, bohemine, CYC202, 3-ATA, NU2058, purvalanol A, BMS-265246, flavopiridol (alvocidib), roniciclib (BAY1000394), P276-

[0383] 00 (riviciclib), dinaciclib (SCH727965), AT7519, seliciclib (roscovitine), AG-024322, PHA- 793887, R547, RGB-286638, AZD-5438, indirubin (couroupitine B), milciclib, PHA-848125AC, or indirubin-5-sulfonic acid, or a pharmaceutically acceptable salt thereof; and

[0384] (iii) one or more pharmaceutically acceptable excipients. 135. The pharmaceutical combination of embodiment 134, comprising an amorphous spray- dried dispersion (ASD) of INX-315.

[0385] 136. The pharmaceutical combination of embodiment 135, wherein INX-315 is between about 20% and about 60% by weight of the ASD.

[0386] 137. The pharmaceutical combination of embodiment 135 or 136, wherein INX-315 is between about 30% and about 50% by weight of the ASD.

[0387] 138. The pharmaceutical combination of any one of embodiments 135-137, wherein INX-315 is about 40% by weight of the ASD.

[0388] 139. The pharmaceutical combination of any one of embodiments 134-138, in a dosage from selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg of INX-315, or a pharmaceutically acceptable salt thereof.

[0389] 140. The pharmaceutical combination of any one of embodiments 135-139, wherein the ASD further comprises a precipitation preventer.

[0390] 141. The pharmaceutical combination of embodiment 140, wherein the precipitation preventer is selected from a cellulose derivative, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethyl cellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, PVP K 30, PVP K 25, PVP VA64, or PVP VA37.

[0391] 142. The pharmaceutical combination of embodiment 140 or 141, wherein the precipitation preventer is HPMCAS-HG.

[0392] 143. The pharmaceutical combination of any one of embodiments 140-142, wherein the precipitation preventer in the ASD is between about 40% and about 80% by weight of the ASD. 144. The pharmaceutical combination of any one of embodiments 140-143, wherein the precipitation preventer in the ASD is about 60% by weight of the ASD.

[0393] 145. Use of an effective amount of the pharmaceutical combination of any one of embodiments 134-144, in the manufacture of a medicament for treating a patient having a CCNE1 amplified cancer.

[0394] 146. A method for treating a patient having a CCNE1 amplified cancer, comprising administering to the patient an effective amount of the pharmaceutical combination of any one of embodiments 134-144.

[0395] 147. Use of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure: or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor for treating a patient having a KRAS mutant cancer.

[0396] 148. Use of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure: or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor in the manufacture of a medicament to treat a patient having a KRAS mutant cancer.

[0397] 149. Use of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, wherein the patient has already received, will receive administration of, or is receiving the RAS inhibitor.

[0398] 150. Use of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to delay acquired resistance to a RAS inhibitor in a patient in need thereof, wherein the patient has already received, will receive administration of, or is receiving the RAS inhibitor. 151. Use of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, wherein the patient has already received or is receiving the RAS inhibitor.

[0399] 152. Use of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to resensitize a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, wherein the patient has already received or is receiving the RAS inhibitor.

[0400] 153. Use of a CDK2 inhibitor compound of structure: pharmaceutically acceptable salt thereof for treating a patient having a KRAS mutant cancer, comprising:

[0401] (i) obtaining a sample from the patient;

[0402] (ii) detecting whether KRAS is mutated in the sample compared with a control sample;

[0403] (iii) if KRAS comprises a mutation, then administering to the patient:

[0404] (a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and

[0405] (b) an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0406] 154. Use of a CDK2 inhibitor compound of structure: in the manufacture of a medicament to treat a patient having a KRAS mutant cancer, comprising:

[0407] (i) obtaining a sample from the patient; (ii) detecting whether KRAS is mutated in the sample compared with a control sample;

[0408] (iii) if KRAS comprises a mutation, then administering to the patient: (a) an effective amount of the CDK2 inhibitor compound INX-315, or a pharmaceutically acceptable salt thereof; and

[0409] (b) an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0410] 155. Use of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof for treating a patient having a KRAS mutant cancer comprising loss of function of p53.

[0411] 156. Use of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat a patient having a KRAS mutant cancer comprising loss of function of p53. 157. Use of a CDK2 inhibitor compound of structure: pharmaceutically acceptable salt thereof for treating a patient having a KRAS mutant cancer with a p53 loss of function mutation, comprising:

[0412] (i) obtaining a sample from the patient;

[0413] (ii) detecting whether the sample has a p53 loss of function mutation compared with a control sample;

[0414] (iii) if the sample comprises a p53 loss of function mutation, then administering to the patient:

[0415] (a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof.

[0416] 158. Use of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat a patient having a KRAS mutant cancer with a p53 loss of function mutation, comprising:

[0417] (i) obtaining a sample from the patient;

[0418] (ii) detecting whether the sample has a p53 loss of function mutation compared with a control sample; (iii) if the sample comprises a p53 loss of function mutation, then administering to the patient:

[0419] (a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof. 159. Use of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure: or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor for treating a patient having a CCNE1 amplified cancer. 160. Use of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure: or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor in the manufacture of a medicament to treat a patient having a CCNE1 amplified cancer. 161. Use of a CDK2 inhibitor compound of structure: pharmaceutically acceptable salt thereof for treating a patient having a CCNE1 amplified cancer, comprising:

[0420] (i) obtaining a sample from the patient; (ii) detecting whether CCNE1 is amplified or overexpressed in the sample compared with a control sample;

[0421] (iii) if CCNE1 is amplified or over expressed, then administering to the patient:

[0422] (a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and (b) an effective amount of a CDK1 inhibitor, or a pharmaceutically acceptable salt thereof.

[0423] 162. Use of a CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat a patient having a CCNE1 amplified cancer, comprising:

[0424] (i) obtaining a sample from the patient;

[0425] (ii) detecting whether CCNE1 is amplified or overexpressed in the sample compared with a control sample;

[0426] (iii) if CCNE1 is amplified or over expressed, then administering to the patient: (a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and

[0427] (b) an effective amount of a CDK1 inhibitor, or a pharmaceutically acceptable salt thereof.

[0428] 163. Use of an effective amount of the pharmaceutical combination of any one of embodiments 119-129 for delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer.

[0429] 164. Use of an effective amount of the pharmaceutical combination of any one of embodiments 119-129 for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof.

[0430] 165. Use of an effective amount of the pharmaceutical combination of any one of embodiments 134-144 for treating a patient having a CCNE1 amplified cancer.

[0431] 166. A cyclin dependent kinase 2 (CDK2) inhibitor compound of structure: or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor for use treating a patient having a KRAS mutant cancer.

[0432] 167. A CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof for use delaying acquired resistance to a RAS inhibitor in a patient in need thereof, wherein the patient has already received, will receive administration of, or is receiving the RAS inhibitor.

[0433] 168. A CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof for use resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, wherein the patient has already received or is receiving the RAS inhibitor.

[0434] 169. A CDK2 inhibitor compound of structure: pharmaceutically acceptable salt thereof for use treating a patient having a KRAS mutant cancer, comprising:

[0435] (i) obtaining a sample from the patient;

[0436] (ii) detecting whether KRAS is mutated in the sample compared with a control sample;

[0437] (iii) if KRAS comprises a mutation, then administering to the patient: (a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and (b) an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0438] 170. A CDK2 inhibitor compound of structure: or a pharmaceutically acceptable salt thereof for use treating a patient having a KRAS mutant cancer comprising loss of function of p53.

[0439] 171. A CDK2 inhibitor compound of structure : pharmaceutically acceptable salt thereof for use treating a patient having a KRAS mutant cancer with a p53 loss of function mutation, comprising:

[0440] (i) obtaining a sample from the patient;

[0441] (ii) detecting whether the sample has a p53 loss of function mutation compared with a control sample;

[0442] (iii) if the sample comprises a p53 loss of function mutation, then administering to the patient:

[0443] (a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof. 172. A cyclin dependent kinase 2 (CDK2) inhibitor compound of structure: or a pharmaceutically acceptable salt thereof, for use in combination or alternation with an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor for treating a patient having a CCNE1 amplified cancer.

[0444] 173. A CDK2 inhibitor compound of structure: pharmaceutically acceptable salt thereof for use treating a patient having a CCNE1 amplified cancer, comprising:

[0445] (i) obtaining a sample from the patient;

[0446] (ii) detecting whether CCNE1 is amplified or overexpressed in the sample compared with a control sample;

[0447] (iii) if CCNE1 is amplified or overexpressed, then administering to the patient:

[0448] (a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and

[0449] (b) an effective amount of a CDK1 inhibitor, or a pharmaceutically acceptable salt thereof. 174. A pharmaceutical combination of any one of embodiments 119-129 for use delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer.

[0450] 175. A pharmaceutical combination of any one of embodiments 119-129 for use resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof. 176. A pharmaceutical combination of any one of embodiments 134-144 for use treating a patient having a CCNE1 amplified cancer.

[0451] EXAMPLES

[0452] Example 1. Use of INX-315 in KRAS Mutant Cancers Introduction

[0453] The various cancer model cell lines that were assayed with certain KRAS mutation characteristics (Cellosaurus Release 49 of May 2024), and some with selected further mutations (e.g., CCNE1, p53), are provided below in Table 2.

[0454] Table 2. Cell Lines

[0455]

[0456] The effect of CDK2 inhibitor compound INX-315 administered alone or in combination with a CDK4 / 6 inhibitor or with a KRAS inhibitor was studied in various KRAS mutant cancer model cell lines.

[0457] Methods

[0458] AGS cells were incubated overnight at 37°C with 5% CO2. Cells were treated (n=3) with a dose curve of INX-315, MRTX-1133, MRTX-1133 + 100 nM INX-315, Palbociclib, or Palbociclib + 100 nM INX-315 and treated for 6 days. CellTiter-Glo was added to the plates and luminescence was read using a CLARIOstar luminometer with 1 sec / well integration.

[0459] Results

[0460] Stomach cancer model AGS cells harbor a mutation which encodes for KRAS G12D as well as a Cyclin El (CCNE1) amplification mutation. AGS 6-Day CTG results were illustrated (FIG. 1). Viabilities were expressed as a ratio of the untreated controls. See assay results in the below table.

[0461] Table 3. AGS 6-Day CTG IC50 Values (FIG. 1)

[0462] Surprisingly, INX-315 administered in combination with a CDK4 / 6 inhibitor (Palbociclib) synergistically inhibited KRAS G12D mutant stomach cancer model AGS cells compared to either compound alone (FIG. 1). Example 2. Comparing INX-315 Efficacy in Independent Studies

[0463] Introduction

[0464] The efficacies observed for CDK2 inhibitor compound INX-315 administered alone or in combination with a KRAS inhibitor or with a CDK4 / 6 inhibitor was compared in independent studies.

[0465] Methods

[0466] KRAS mutant cancer cell lines were plated at a cell density to optimize CTG readings at 5 days of treatment and maintained in media appropriate for the cell line. Cells were plated and incubated overnight at 37°C with 5% CO2. Cells were treated in triplicate with the following 9- point dose curves: INX-315, palbociclib (CDK4 / 6 inhibitor), RMC-6236 (pan RAS inhibitor), palbociclib dose curve + 100 nM INX-315, RMC-6236 + 100 nM INX-315. Cells were treated for 5 days before CellTiter-Glo was added, incubated for 20 minutes, and then luminescence read using an EnVision Multi Label Reader.

[0467] Results

[0468] Non-small cell lung cancer (NSCLC) model A549 cells harbor a mutation which encodes for KRAS G12S. A549 6-Day CTG results were illustrated and compared (FIG. 2A-2B). Viabilities were expressed as a ratio of the untreated controls. See assay results in the below tables.

[0469] Table 4. A549 6-Day CTG IC50 Values of Independent Study 1 (FIG. 2A)

[0470] Table 5. A549 6-Day CTG IC50 Values of Independent Study 2 (FIG. 2B) Stomach cancer model AGS cells harbor a mutation which encodes for KRAS G12D as well as a Cyclin El (CCNE1) amplification mutation. AGS 6-Day CTG results were illustrated and compared (FIG. 3A-3B). Viabilities were expressed as a ratio of the untreated controls. See assay results in the below tables.

[0471] Table 6. AGS 6-Day CTG IC50 Values of Independent Study 1 (FIG. 3 A)

[0472] Table 7. AGS 6-Day CTG IC50 Values of Independent Study 2 (FIG. 3B)

[0473] Pancreatic cancer model MIA PaCa-2 cells harbor a mutation which encodes for KRAS G12C. MIA PaCa-2 6-Day CTG results were illustrated and compared (FIG. 4). Viabilities were expressed as a ratio of the untreated controls. See assay results in the below table.

[0474] Table 8. MIA PaCa-2 6-Day CTG IC50 Values of Independent Study 1 (FIG. 4)

[0475] Surprisingly, the addition of the CDK2 inhibitor INX-315 in combination with a CDK4 / 6 inhibitor consistently and synergistically inhibited a variety of KRAS mutant cell lines compared to either compound alone, including models of KRAS mutant NSCLC, KRAS mutant stomach cancer, and KRAS mutant pancreatic cancer. Example 3. INX-315 enhances CDK4 / 6 inhibitor effectiveness in a dose-dependent manner in sensitive KRAS mutant cells

[0476] Introduction

[0477] The effect of increasing doses of CDK2 inhibitor compound INX-315 administered in combination with a CDK4 / 6 inhibitor (Palbociclib) was studied in various KRAS mutant cancer model cell lines.

[0478] Methods

[0479] Panel cells were seeded at 1000 cells per well (corning 96-well white wall plates) and grown in DMEM with GlutaMAX and 10% fetal bovine serum (FBS). HCT 116 cells were seeded at 100 cells per well and grown in McCoy’s 5Amedia with GlutaMAX and 10% FBS. MIAPaca2 cells were seeded at 1000 cells per well and grown in DMEM with GlutaMAX, 10% FBS, and 2.5% equine serum. Cells were incubated overnight at 37°C with 5% CO2. Cells were treated (n=3) with a dose curve of INX-315, palbociclib and palbociclib plus 10, 30, 100, 300, or 1000 nM INX-315. Cells were treated for 6 days before CellTiter-Glo was added to the plates and luminescence was read using a CLARIOstar luminometer with 1 sec / well integration.

[0480] Results

[0481] MIA PaCa2 6-Day CTG results were illustrated (FIG. 5A). Viabilities were expressed as a ratio of the untreated controls. See assay results in the below table.

[0482] Table 9. MIAPaCa2 6-Day CTG IC50 Values

[0483] Pancreatic cancer model Panel cells harbor a mutation which encodes for KRAS G12D.

[0484] Panel 6-Day CTG results were illustrated (FIG. 5B). Viabilities were expressed as a ratio of the untreated controls. See assay results in the below table. Table 10. Panel 6-Day CTG IC50 Values

[0485] Colorectal cancer model HCT 116 cells harbor a mutation which encodes for KRAS G13D.

[0486] HCT 116 6-Day CTG results were illustrated (FIG. 5C). Viabilities were expressed as a ratio of the untreated controls. See assay results in the below table.

[0487] Table 11 . HCT 116 6-Day CTG IC50 Values

[0488] INX-315 improved CDK4 / 6 inhibitor effectiveness in a dose dependent manner in all KRAS mutant cell lines tested, although to a greater extent in pancreatic KRAS G12C cancer model MIA PaCa-2 cells and colorectal cancer KRAS G13D model HCT 116 cell lines.

[0489] Example 4. In Silica Biomarker Analysis demonstrates INX-315 increases KRAS Mutant Cancer Sensitivity to CDK4 / 6 Inhibitor Treatment

[0490] Introduction

[0491] The effect of certain biomarkers and their association with efficacy of CDK2 inhibitor compound INX-315 administered alone or in combination with a CDK4 / 6 inhibitor was analyzed in silica.

[0492] Methods

[0493] The pM logl0(IC50) of palbociclib and the pM logl0(IC50) of palbociclib + 100 nM INX- 315 combination treatment were compared. Also, the AUC of palbociclib and the AUC of palbociclib + 100 nM INX-315 combination treatment were compared. Dotted lines show 500 nM IC50 as a marker for sensitivity to treatment. Cell lines A-427, LoVb, LS 513, NCI-H460, HCT 116, AGS, COR-L23, Pane 08.13, and A549 have functional p53, while the rest have p53 loss of function. Shapes represent the functional status of pl6. NCLH358, SW-1463, NCT-H2009, T84, OVCAR-8, LoVo, SW-620, NCI-H23, and HPAF-II have functional pl6, while the rest have pl6 loss of function. NCI-H2009, OVCAR-8 and T84 have Rb loss of function, while the rest have functional Rb. OVCAR-8 is ovary cancer cell line. AGS is stomach cancer cell line. A-427, NCI- H358, NCI-H2009, NCI-H460, COR-L23, NCI-H23, and A549 are NSCLC (non-small cell lung cancer) cell lines. T84, SW-1463, HCT-15, LoVo, LS 513, SW-620, DLD-1, and HCT 116 are CRC (colorectal cancer) cell lines. Pane 02.03, KP4, Capan-1, HPAF-II, PANC-1, Pane 08.13, AsPC-1, and MIA PaCa-2 are Pancreas cancer cell lines.

[0494] Results

[0495] Eight cell lines became sensitive with the addition of 100 nM INX-315 (NCI-H358, NCI- H460, HCT 116, HPAF-II, AGS, COR-L23, A549, and MIA PaCa-2), while four additional cell lines have inhibitory concentration values significantly decreased by the addition of INX-315 (LS 513, SW-620, DLD-1, and NCI-H23) (FIG. 6A). Two cell lines that are sensitive to palbociclib (A-427, KP4) have an improved response with the addition of INX-315. The improvement in response to INX-315 was not associated with cancer cell origin or biomarker status in the cell lines tested (FIG. 6B-6C).

[0496] Example 5. In Silica Biomarker Analysis Demonstrates Biomarkers Predict Beneficial Response to INX-315 and RAS Inhibitor Combinations

[0497] Introduction

[0498] The effect of certain biomarkers and their association with efficacy of CDK2 inhibitor compound INX-315 administered alone or in combination with a RAS inhibitor was analyzed in silica.

[0499] Methods

[0500] The pM logl0(IC50) of RMC-6236 and the pM logl0(IC50) of RMC-6236 + 100 nM INX-315 combination treatment were compared. OVCAR-8 is ovary cancer cell line. AGS is stomach cancer cell line. A-427, NCLH358, NCI-H2009, NCI-H460, COR-L23, NCLH23, and A549 are NSCLC (non-small cell lung cancer) cell lines. T84, SW-1463, HCT-15, LoVo, LS 513, SW-620, DLD-1 , and HCT 116 are CRC (colorectal cancer) cell lines. Pane 02.03, KP4, Capan-1 , HPAF-II, PANC-1, Pane 08.13, AsPC-1, and MIA PaCa-2 are Pancreas cancer cell lines.

[0501] Results

[0502] The influence of Rb and pl 6 status on the ratio of areas under the curve of the combination of INX-315 and RMC-6236 to RMC-6236 alone was inconclusive (FIG. 7A-7B), while cells with loss of function of p53 more frequently benefit from INX-315 / RMC-6236 combination treatment (FIG. 7C). This suggests that cells which lack functional p53 respond better to an INX-315 and RAS inhibitor combination treatment.

[0503] Example 6. INX-315 Delays Acquired Resistance to RAS inhibitors in KRAS Mutant Cancer Introduction

[0504] The inhibitory effect of CDK2 inhibitor compound INX-315 administered alone or in combination with a KRAS inhibitor (e.g., RMC-6236) or with a CDK4 / 6 inhibitor (e.g., palbociclib) on colony outgrowth was studied in various KRAS mutant cancer model cell lines.

[0505] Methods

[0506] HCT 116 cells were seeded at 2,000 cells / well in 3, 12 well plates (Corning) and grown in McCoy’s 5A with GlutaMAX and 10% fetal bovine serum (FBS). Cells were incubated overnight at 37°C with 5% CO2. Plates were treated as replicates, with column 1 being treated with 0.1% DMSO, column 2 treated with 100 nM palbociclib and 300 nM INX-315. Columns 3 and 4 were treated with 10 nM RMC-6236 but with column 4 additionally being treated with 300 nM INX- 315. Treatments were refreshed every 3-4 days and cell densities monitored. Plates were collected and stained using crystal violet (0.5% crystal violet, 20% methanol) at the indicated time points.

[0507] A549 cells were seeded at 5,000 cells / well in 3, 12 well plates (Coming) and grown in F- 12K media with GlutaMAX and 10 % fetal bovine serum (FBS). Cells were incubated overnight at 37°C with 5% CO2. Plates were treated as replicates, with column 1 being treated with 0.1% DMSO, column 2 treated with 100 nM palbociclib and 300 nM INX-315. Columns 3 and 4 were treated with 10 nM RMC-6236 but with column 4 additionally being treated with 300 nM INX- 315. Treatments were refreshed every 3-4 days and cell densities monitored. Plates were collected and stained using crystal violet (0.5% crystal violet, 20% methanol) at the indicated time points.

[0508] MIA Paca 2 cells were seeded at 5000 cells / well in 3, 12 well plates (Corning) and grown in DMEM with GlutaMAX, 10% FBS, and 2.5% equine serum. Cells were incubated overnight at 37°C with 5% CO2. Plates were treated as replicates, with column 1 being treated with 0.1% DMSO, column 2 treated with 100 nM palbociclib and 300 nM INX-315. Columns 3 and 4 were treated with 10 nM RMC-6236 but with column 4 additionally being treated with 300 nM INX- 315. Treatments were refreshed every 3-4 days and cell densities monitored. Plates were collected and stained using crystal violet (0.5% crystal violet, 20% methanol) at the indicated time points.

[0509] Results

[0510] Cell colony assay results for HCT 116 cell, A549 cell, and MIA PaCa-2 cell lines were illustrated (FIG. 8A-8C, respectively). INX-315 delayed outgrowth of cells treated with RMC- 6236 in HCT 116 and A549 cells (FIG. 8A-8B), while RMC-6236 had some colonies growing out at the endpoint in MIA PaCa-2 cells (FIG. 8C). In HCT 116 and A549 cells, the combination of Palbociclib and INX-315 reduced cell growth greater than other treatments (FIG. 8A-8B), while in MIA PaCa-2 cells the combination of Palbociclib and INX-315 eliminated cells altogether following treatment end (FIG. 8C). The combination of INX-315 in combination with RMC-6236 had no colonies growing out in MIAPaCa 2 cells as well (FIG. 8C).

[0511] As shown, the addition of INX-315 drastically improved cell sensitivity to combined treatment compared to single RAS inhibitor treatment alone, indicating a suppression of RAS inhibitor resistance in KRAS mutant cell lines. Similarly, the combination of INX-315 and a CDK4 / 6 inhibitor prevented colony outgrowth at levels exceeding RAS inhibitor treatment alone, further validating the efficacy of CDK2 inhibitor and CDK4 / 6 inhibitor combination treatments in KRAS mutant cancer.

[0512] Example 7. INX-315 Induces Necrosis

[0513] Introduction

[0514] The necrotic effect of CDK2 inhibitor compound INX-315 administered alone or in combination with a KRAS inhibitor (e.g., RMC-6236) or with a CDK4 / 6 inhibitor (e.g., palbociclib) was studied in various KRAS mutant cancer model cell lines.

[0515] Methods

[0516] HCT 116 cells were seeded at 500 cells per well (Corning 96-well white wall plates) and grown in McCoy’s 5A with GlutaMAX and 10% fetal bovine serum (FBS). Cells were incubated overnight at 37°C with 5% CO2. Cells were treated (n=2 for INX-315, n=3 for RMC-6236 conditions, n= 3 for palbociclib conditions) with a dose curve of INX-315, RMC-6236, or RMC- 6236 + 100 nM INX-315, palbociclib, or palbociclib + 100 nM INX-315 and treated for 48 hours. Cells were incubated with Cell Tox Green (Promega G8743), to show any necrosis. A follow up CTG assay was performed using manufacturer’s instructions.

[0517] Results

[0518] Necrotic signals were expressed as a ratio of the untreated controls. Surprisingly, administration of INX-315 alone induced necrosis, whereas neither RMC-6236 nor palbociclib alone did not (FIG. 9A). Cell Tox Green (CTG) indicates the lower signal is due to inhibition of cellular proliferation, not cell death (FIG. 9B).

[0519] Example 8. INX-315 Cell Cycle Assay

[0520] Introduction

[0521] The effect of CDK2 inhibitor compound INX-315 administered alone or in combination with a RAS inhibitor (e.g., RMC-6236) or with a CDK4 / 6 inhibitor (e.g., palbociclib) to induce cell cycle phase shifts in cell populations was studied in various KRAS mutant cancer model cell lines. Methods

[0522] HCT 116 cells were seeded at 50,000 cells per well (corning 6 well tissue culture plate) and grown in McCoy’s 5 A with GlutaMAX and 10% fetal bovine serum (FBS). AGS cells were seeded at 100,000 cells per well and grown in F-12K media with GlutaMAX and 10% FBS. MIA PaCa-2 cells were seeded at 100,000 cells per well and grown in DMEM with GlutaMAX, 10% FBS, and 2.5% equine serum. Cells were incubated overnight at 37°C with 5% CO2. Cells were treated with 0.1% DMSO; INX-315 at 30, 100, 300, or 1000 nM; 100 nM palbociclib, palbociclib + 100 or 300 nM INX-315; 3 nM RMC-6236, RMC-6236 + 100 or 300 nM INX-315 (n=2). Cells were incubated for 47 hours before 10 pM EdU was added to the media. After one additional hour, cells were collected and fixed in 4% paraformaldehyde. Cells were incubated with Alexa 488 azide dye as described by Thermo Scientific. Cells were then incubated with FarRed dye and RNase. Cells were analyzed on a BD Celesta and data compiled using FloJo and GraphPad.

[0523] Results

[0524] Administration of INX-315 alone did not substantially alter the frequency of cell populations in various cell cycle phases in MIA PaCa-2 cells, whereas the combination of INX- 315 with either a RAS inhibitor or with a CDK4 / 6 inhibitor increased the percentage of cells in G1 phase, and nearly eliminated cells in S phase (FIG. 10A). Similarly, in AGS and HCT 116 cells only INX-315 / RAS inhibitor and INX-315 / CDK4 / 6 inhibitor combination therapies substantially increased the frequency of cells in G1 phase while reducing the frequency of cells in S phase (FIG. 10B-10C). It should be noted that in AGS and HCT 116 cells, high concentrations of INX-315 induced similar increases in G1 phase cells with concomitant decreases in S-phase cells (FIG. 10B- 10C).

[0525] Example 9. INX-315 Cell Cycle Marker Analysis

[0526] Introduction

[0527] The effect of CDK2 inhibitor compound INX-315 administered alone or in combination with a RAS inhibitor (e.g., RMC-6236) or with a CDK4 / 6 inhibitor (e.g., palbociclib) to induce changes in levels of cell cycle markers was studied in various KRAS mutant cancer model cell lines. Methods

[0528] HCT 116 cells were seeded at 50,000 cells per well (corning 6 well tissue culture plate) and grown in McCoy’s 5A with GlutaMAX and 10% fetal bovine serum (FBS). AGS cells were seeded at 100,000 cells per well and grown in F-12K media with GlutaMAX and 10% FBS. Cells were treated with 0.1% DMSO; INX-315 at 30, 100, 300, or 1000 nM; 100 nM palbociclib, palbociclib + 100 or 300 nM INX-315; 3 nM RMC-6236, RMC-6236 + 100 or 300 nM INX-315 (z / 2) Cells were incubated for 48 hours before the media was aspirated, cells washed twice with cold PBS, and lysed with 100 pL of RIPA buffer containing phosphatase and protease inhibitors. Lysates were clarified by centrifugation at 12 kxg for 15 min at 4°C and supernatants transferred to clean tubes. ABCA assay was performed to determine the protein concentration of each lysate. A total of 20 to 30 pg of protein was mixed with sample buffer and reducing agent before being boiled and run on a 4-12% SDS-PAGE. Protein was transferred to a nitrocellulose membrane and blocked with LI-COR blocking buffer for 1 hour. Membranes were incubated overnight in primary antibody at 4°C. Following 3 washes with TBST, membranes were incubated for 60 minutes in LI-COR secondary antibodies. Following 3 washes in TBST, and one TBS wash, membranes were scanned using a LI-COR OdysseyCLx. Image studio was used for image analysis.

[0529] Results

[0530] As shown in immunoblots of samples of stomach cancer model AGS cells which harbor a mutation encoding KRAS G12D as well as a Cyclin El (CCNE1) amplification, INX-315 combination treatment groups induced decreased phosphorylated Rb compared to INX-315 administered alone, whereas Rb levels appeared mostly unchanged across all treatment groups (FIG. 11 A). Further, decreased levels of survivin and phosphorylated FoxMl were observed in the INX-315 combination groups compared to administration of INX-315 alone (FIG. 11A-11B). This suggests that the enhanced efficacy of treatment combinations comprising INX-315 may be due to profound suppression of Rb phosphorylation coupled with enhancement of a pro-apoptotic phenotype when compared to single agent treatment.

[0531] Similarly, INX-315 combination treatment groups induced decreased phosphorylated Rb compared to INX-315 administered alone in HCT 116 cells (KRAS G13D colorectal cancer cells), while Rb levels were unchanged across all treatment groups (FIG. 12A). Additionally, decreased levels of survivin, phosphorylated FoxMl, and phosphorylated ERK were observed in the INX- 315 combination groups compared to administration of INX-315 alone in HCT 116 cells (FIG. 12A-12B). This is an independent observation of INX-315 combination treatments suppress Rb activation and enhance pro-apoptotic phenotypes relative to single agent treatments. Interestingly, the combination of INX-315 and CDK4 / 6 inhibitor (Palbociclib) induced a phenomenon of increased steady-state levels of Cyclin El protein in both AGS cells and HCT 116 cells (FIG. 11 A, 12A), which suggests that KRAS mutant cancer cells become increasingly reliant on the CDK2- CCNE1 pathway as an amplification loop mechanism to iteratively enhance sensitivity to CDK2 inhibitor INX-315 treatment.

[0532] Example 10. Synthesis of INX-315

[0533] The synthesis of INX-315 is provided in WO 2021 / 236650, published November 25, 2021 and U.S. Patent No. 11,643,416 (designated as Compound 3 in the patent).

[0534] Synthesis of 4-((3'-oxo-2',3'-dihydro-l'H-spiro[cyclohexane-l,4'- pyrimido[5',4':4,5]pyrrolo[2,l-c][l,2,4]triazin]-7'-yl)amino)benzenesulfonamide

[0535]

[0536] Compound 3

[0537] Step 1: To a solution of ethynyltrimethylsilane (30 g, 305.94 mmol) in anhydrous THF (500 mL), under N2 atmosphere, was added dropwise to n-BuLi (147 ml, 2.5 mol in THF, 367.5 mmol) at - 78°C, over 30 min. After the addition, the reaction was stirred at -78°C for 20 min. Then to the reaction solution was added dropwise to a solution of intermediate 1 (105 g, 456.26 mmol) in anhydrous THF (300 mL) over 60 min. After the addition, the reaction was allowed to gradually warm to -20°C and the reaction was allowed to stir at -20°C for 30 min. The reaction was quenched with saturated NH4CI solution (100 mL) and water (300 mL), extracted with EA (200 mL x 2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica column chromatography to afford intermediate 2 (60 g, 182.83 mmol) as oil.

[0538] Step 2: To a solution of intermediate 2 (60 g, 182.83 mmol) in THF (300 mL) was added a solution of TBAF trihydrate (72 g, 228.20 mmol) in THF (300 mL) at -20°C. After the addition, the reaction was stirred at -20°C for 60 min. The reaction mixture was quenched with saturated NH4CI solution (100 mL) and water (400 mL), extracted with EA (300 mL x 2). The combined organic phase was dried over Na2SC>4, filtered and concentrated in vacuo. The resulting residue was purified by silica column chromatography to afford intermediate 3 (36 g, 140.55 mmol).

[0539] Step 3: To a solution of intermediate 3, intermediate 4, Cui (1.1 g, 5.79 mmol), Pd(PPh3)2C12 (4.1 g, 5.86 mmol), diisopropylamine (17.6 g, 174.05 mmol) were mixed in DMF at room temperature overnight. The reaction was quenched with water (500 mL), and extracted with EA (500 mL x 3). The combined organic phase was washed with water (500 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica column chromatography to afford intermediate 5 (28 g, 69.64 mmol). LC-MS (ESI+): m / z 403 [M + H]+. Step 4: To a solution of intermediate 5 (2 g, 4.97 mmol) in DMF (20 mL), under N2 atmosphere, was added intermediate 6 (1.2 g, 7.64 mmol) and NaHCCL (1.25 g, 14.93 mmol). The reaction mixture was stirred at 60°C overnight. Then the reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with EA (30 mL x 3). The combined organic phase was dried over Ha^SCh, fdtered and concentrated in vacuo. The resulting residue was purified by silica column chromatography to afford intermediate 7 (1.2 g, 2.29 mmol). LC-MS (ESI+): m / z 524 [M + H]+.

[0540] Step 5: To a solution of intermediate 7 (1.2 g, 2.29 mmol) in THF (15 mL) was added a solution of TBAF (1.2 mL, 1 mol in THF, 1.2 mmol). The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature quenched with water (30 mL), and extracted with EA (30 mL x 3). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica column chromatography to afford intermediate 8 (300 mg, 0.57 mmol). LC-MS (ESI+): m / z 524 [M + H]+.

[0541] Step 6: To a solution of intermediate 8 (2 g, 3.82 mmol) in DMAc (30 mL) was added CS2CO3 (4 g, 12.28 mmol). The reaction mixture was stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature, quenched with water (60 mL), and extracted with EA (20 mL x 3). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica column chromatography to afford intermediate 9 (320 mg, 0.82 mmol). LC-MS (ESI+): m / z 392 [M + H]+.

[0542] Step 7: To a solution of intermediate 9 (50 mg, 0.13 mmol) in DMF (2 mL), under N2 atmosphere, was added intermediate 10 (24 mg, 0.14 mmol), Pd(OAc)2 (2.8 mg, 0.013 mmol), X-Phos (24 mg, 0.05 mmol) and AcOK (38 mg, 0.38 mmol). The reaction was stirred at 80°C for 5 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with DCM:MeOH =10:1 (20 mLx 3). The combined organic phase was dried overMgSCh, filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC to afford intermediate 11 (43 mg, 0.082mmol). LC-MS (ESI+): m / z 528 [M + H]+.

[0543] Step 8: To a solution of intermediate 11 (20 mg, 0.038 mmol) in DCM (2 mL) was added TFA (0.2 mL). The reaction was stirred at RT for 2 hours. The reaction mixture was quenched with saturated NaHCCL solution (10 mL), and extracted with DCM:MeOH =10:1 (10 mL x 3). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC to afford Compound 3 (2.1 mg, 0.005 mmol). LC-MS (ESI+): m / z 428 [M + H]+; 1H NMR (300 MHz, CD3OD): <58.48 (s, 1H), 7.92 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 9.0 Hz, 2H), 5.80 (s, 1H), 2.49 - 2.38 (m, 2H), 2.15 - 1.97 (m, 6H), 1.90 - 1.81 (m, 1 H), 1.70 - 1.61 (m, 1 H).

[0544] This specification has been described with reference to embodiments of the invention. One of ordinary skill in the art, however, appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of the invention.

Claims

CLAIMSWe claim:

1. A method for treating a patient having a KRAS mutant cancer, comprising administering to the patient an effective amount of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor.

2. The method of claim 1, wherein the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, riboci clib, abemaciclib, trilaciclib, lerociclib, dalpiciclib, BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP-3287), LY5219, PF-07220060, and ON-123300.

3. The method of claim 1 or 2, wherein the CDK4 / 6 inhibitor is palbociclib.

4. The method of any one of claims 1-3, wherein the KRAS mutant cancer comprises a mutation encoding a KRAS substitution.

5. The method of claim 4, wherein the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution.

6. The method of claim 4 or 5, wherein the KRAS substitution is a KRAS G12 substitution.

7. The method of claim 5 or 6, wherein the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V.

8. The method of any one of claims 5-7, wherein the KRAS G12 substitution is a KRAS G12C substitution.

9. The method of any one of claims 5-7, wherein the KRAS G12 substitution is a KRAS G12D substitution.

10. The method of any one of claims 5-7, wherein the KRAS G12 substitution is a KRAS G12S substitution.

11. The method of claim 5 or 6, wherein the KRAS substitution is a KRAS G13 substitution.

12. The method of claim 5 or 6, wherein the KRAS substitution is a KRAS Q61 substitution.

13. The method of claim 12, wherein the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R.

14. The method of claim 5 or 6, wherein the KRAS substitution is a KRAS D162 substitution.

15. The method of claim 14, wherein the KRAS D162 substitution is a KRAS D162K substitution.

16. The method of any one of claims 1-3, wherein the KRAS mutant cancer comprises a KRAS amplification.

17. The method of any one of claims 1-16, wherein the KRAS mutant cancer comprises loss of function of p53.

18. The method of any one of claims 1-17, wherein the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer.

19. The method of any one of claims 1-17, wherein the KRAS mutant cancer is colorectal cancer.

20. The method of any one of claims 1 -17, wherein the KRAS mutant cancer is non-small cell lung cancer (NSCLC).

21. The method of any one of claims 1-17, wherein the KRAS mutant cancer is pancreatic cancer.

22. The method of any one of claims 1-21, wherein the KRAS mutant cancer has progressed following a prior regimen comprising a RAS inhibitor.

23. The method of any one of claims 1-22, wherein the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

24. A method for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, wherein the patient has already received, will receive administration of, or is receiving the RAS inhibitor.

25. The method of claim 24, further comprising administering to the patient an effective amount of a RAS inhibitor.

26. The method of claim 24 or 25, wherein the RAS inhibitor is a KRAS inhibitor.

27. The method of claim 26, wherein the KRAS inhibitor binds to or is selective for KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G12R.

28. The method of claim 26, wherein the KRAS inhibitor binds to or is selective for KRAS Q61H, KRAS Q61R, KRAS Q61L, KRAS Q61K, KRAS Q61P, or KRAS Q61E.

29. The method of claim 26, wherein the KRAS inhibitor is a pan-KRAS inhibitor.

30. The method of claim 20, wherein the KRAS inhibitor is an inhibitor of GDP -bound KRAS.

31. The method of claim 30, wherein the GDP -bound KRAS inhibitor is selected from RM- 018, RMC-6291, RMC-6236, BI-2852, BI-2493, BI-0474, or BI-2865.

32. The method of claim 26, wherein the KRAS inhibitor is selected fromor a pharmaceutically acceptable salt thereof.

33. The method of claim 24 or 25, wherein the RAS inhibitor is selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D- 1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC- 3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL- 15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the RAS inhibitor is MRTX-1133.

35. The method of claim 33, wherein the RAS inhibitor is RMC-6236.

36. The method of any one of claims 24-35, wherein the patient has a KRAS mutant cancer.

37. The method of claim 36, wherein the KRAS mutant cancer comprises a mutation encoding a KRAS substitution.

38. The method of claim 37, wherein the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution.

39. The method of claim 37 or 38, wherein the KRAS substitution is a KRAS G12 substitution.

40. The method of claim 38 or 39, wherein the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V.

41. The method of any one of claims 38-40, wherein the KRAS G12 substitution is a KRAS G12C substitution.

42. The method of any one of claims 38-40, wherein the KRAS G12 substitution is a KRAS G12D substitution.

43. The method of any one of claims 38-40, wherein the KRAS G12 substitution is a KRAS G12S substitution.

44. The method of claim 37 or 38, wherein the KRAS substitution is a KRAS G13 substitution.

45. The method of claim 37 or 38, wherein the KRAS substitution is a KRAS Q61 substitution.

46. The method of claim 45, wherein the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R.

47. The method of claim 37 or 38, wherein the KRAS substitution is a KRAS D162 substitution.

48. The method of claim 47, wherein the KRAS D162 substitution is a KRAS D162K substitution.

49. The method of claim 36, wherein the KRAS mutant cancer comprises a KRAS amplification.

50. The method of any one of claims 36-49, wherein the KRAS mutant cancer further comprises cyclin El (CCNE1) overexpression or amplification.

51. The method of any one of claims 36-50, wherein the KRAS mutant cancer comprises loss of function of p53.

52. The method of any one of claims 36-51, wherein the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer.

53. The method of any one of claims 36-51, wherein the KRAS mutant cancer is colorectal cancer.

54. The method of any one of claims 36-51, wherein the KRAS mutant cancer is non-small cell lung cancer (NSCLC).

55. The method of any one of claims 36-51, wherein the KRAS mutant cancer is pancreatic cancer.

56. The method of any one of claims 36-55, wherein the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

57. A method for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, wherein the patient has already received or is receiving the RAS inhibitor.

58. The method of claim 57, further comprising administering to the patient an effective amount of a RAS inhibitor.

59. The method of claim 57 or 58, wherein the RAS inhibitor is a KRAS inhibitor.

60. The method of claim 59, wherein the KRAS inhibitor binds to or is selective for KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G12R.

61. The method of claim 59, wherein the KRAS inhibitor binds to or is selective for KRAS Q61H, KRAS Q61R, KRAS Q61L, KRAS Q61K, KRAS Q61P, or KRAS Q61E.

62. The method of claim 59, wherein the KRAS inhibitor is a pan-KRAS inhibitor.

63. The method of claim 59, wherein the KRAS inhibitor is an inhibitor of GDP -bound KRAS.

64. The method of claim 63, wherein the GDP-bound KRAS inhibitor is selected from RM- 018, RMC-6291, RMC-6236, BI-2852, BI-2493, BI-0474, or BI-2865.

65. The method of claim 59, wherein the KRAS inhibitor is selected fromor a pharmaceutically acceptable salt thereof.

66. The method of claim 58, wherein the RAS inhibitor is selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK- 1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI- 1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX- 4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BL2852, BI-2493, YL-15293, GEC255, SY- 5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, and BI-2865, or a pharmaceutically acceptable salt thereof.

67. The method of claim 66, wherein the RAS inhibitor is MRTX-113368. The method of claim 66, wherein the RAS inhibitor is RMC-6236.

69. The method of any one of claims 57-68, wherein the KRAS mutant cancer comprises a mutation encoding a KRAS substitution.

70. The method of claim 69, wherein the KRAS substitution is a KRAS G12 substitution, a KRAS G13 substitution, a KRAS Q61 substitution, or a KRAS DI 62 substitution.71 . The method of claim 69 or 70, wherein the KRAS substitution is a KRAS G12 substitution.

72. The method of claim 70 or 71, wherein the KRAS G12 substitution is selected from G12C, G12D, G12R, G12S, or G12V.

73. The method of any one of claims 70-72, wherein the KRAS G12 substitution is a KRAS G12C substitution.

74. The method of any one of claims 70-72, wherein the KRAS G12 substitution is a KRAS G12D substitution.

75. The method of any one of claims 70-72, wherein the KRAS G12 substitution is a KRAS G12S substitution.

76. The method of any one of claim 69 or 70, wherein the KRAS substitution is a KRAS G13 substitution.

77. The method of claim 69 or 70, wherein the KRAS substitution is a KRAS Q61 substitution.

78. The method of claim 77, wherein the KRAS Q61 substitution is selected from Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R.

79. The method of claim 69 or 70, wherein the KRAS substitution is a KRAS DI 62 substitution.

80. The method of claim 79, wherein the KRAS DI 62 substitution is a KRAS D162K substitution.

81. The method of any one of claims 57-68, wherein the KRAS mutant cancer comprises a KRAS amplification.

82. The method of any one of claims 57-81, wherein the KRAS mutant cancer further comprises cyclin El (CCNE1) overexpression or amplification.

83. The method of any one of claims 57-82, wherein the KRAS mutant cancer comprises loss of function of p53.

84. The method of any one of claims 57-83, wherein the KRAS mutant cancer is selected from adenocarcinoma, cholangiocarcinoma, colon cancer, colonic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, esophageal carcinoma, gastric adenocarcinoma, gastric cancer, high-grade serous carcinoma (HGSC), lung cancer, lung adenocarcinoma (LU AD), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), squamous cell carcinoma, or stomach cancer.

85. The method of any one of claims 57-83, wherein the KRAS mutant cancer is colorectal cancer.

86. The method of any one of claims 57-83, wherein the KRAS mutant cancer is non-small cell lung cancer (NSCLC).

87. The method of any one of claims 57-83, wherein the KRAS mutant cancer is pancreatic cancer.

88. The method of any one of claims 57-87, wherein the KRAS mutant cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

89. A method for treating a patient having a KRAS mutant cancer, comprising:(i) obtaining a sample from the patient;(ii) detecting whether KRAS is mutated in the sample compared with a control sample;(iii) if KRAS comprises a mutation, then administering to the patient:(a) an effective amount of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof; and(b) an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

90. A method for treating a patient having a KRAS mutant cancer comprising loss of function of p53, comprising administering to the patient an effective amount of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof.

91. A method for treating a patient having a KRAS mutant cancer with a p53 loss of function mutation, comprising:(i) obtaining a sample from the patient;(ii) detecting whether the sample has a p53 loss of function mutation compared with a control sample;(iii) if the sample comprises a p53 loss of function mutation, then administering to the patient:(a) an effective amount of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof.

92. The method of claim 90 or 91, further comprising administering to the patient an effective amount of a RAS inhibitor.

93. The method of claim 92, wherein the RAS inhibitor is a KRAS inhibitor.

94. The method of claim 93, wherein the KRAS inhibitor binds to or is selective for KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, or KRAS G12R.

95. The method of claim 93, wherein the KRAS inhibitor binds to or is selective for KRAS Q61H, KRAS Q61R, KRAS Q61L, KRAS Q61K, KRAS Q61P, or KRAS Q61E.

96. The method of claim 93, wherein the KRAS inhibitor is a pan-KRAS inhibitor.

97. The method of claim 93, wherein the KRAS inhibitor is an inhibitor of GDP-bound KRAS.

98. The method of claim 97, wherein the GDP-bound KRAS inhibitor is selected from RM- 018, RMC-6291, RMC-6236, BI-2852, BI-2493, BI-0474, or BI-2865.

99. The method of claim 92 or 93, wherein the RAS inhibitor is selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK-1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D- 1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI-1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC- 3116, BDTX-4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY-5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof.

100. The method of any one of claims 1-99, wherein the KRAS mutation is determined with a test selected from Agilent Resolution ctDx FIRST assay, cobas KRAS Mutation Test, FoundationOne CDx, Guardant360 CDx, ONCO / Reveal Dx Lung & Colon Cancer Assay(O / RDx-LCCA), therascreen KRAS RGQ PCR Kit, Praxis Extended RAS Panel, or a combination thereof.

101. A method for treating a patient having a CCNE1 amplified cancer, comprising administering to the patient an effective amount of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor.

102. A method for treating a patient having a CCNE1 amplified cancer, comprising:(i) obtaining a sample from the patient;(ii) detecting whether CCNE1 is amplified or overexpressed in the sample compared with a control sample;(iii) if CCNE1 is amplified or over expressed, then administering to the patient:(a) an effective amount of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof; and(b) an effective amount of a CDK1 inhibitor, or a pharmaceutically acceptable salt thereof.

103. The method of claim 101 or 102, wherein the CDK1 inhibitor is a CDKl-specific inhibitor.

104. The method of claim 103, wherein the CDKl-specific inhibitor is selected from RO-3306, CGP-74514A, or BEY1107 (avotaciclib).

105. The method of 103 or 104, wherein the CDKl-specific inhibitor is RO-3306.

106. The method of claim 102, wherein the CDK1 inhibitor is a pan-CDK inhibitor.

107. The method of claim 106, wherein the pan-CDK inhibitor is selected from alsterpaullone, kenpaullone, CVT-313, staurosporine, JNJ-7706621, olomoucine, SU9516, CDKi277, bohemine, CYC202, 3-ATA, NU2058, purvalanol A, BMS-265246, flavopiridol (alvocidib), roniciclib (BAY1000394), P276-00 (riviciclib), dinaciclib (SCH727965), AT7519, seliciclib (roscovitine), AG-024322, PHA-793887, R547, RGB-286638, AZD-5438, indirubin (couroupitine B), milciclib, PHA-848125AC, or indirubin-5-sulfonic acid.

108. The method of any one of claims 101-107, wherein the CCNE1 amplified cancer is selected from ovarian cancer, uterine cancer, uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC), ovarian cancer, ovarian serous cystadenocarcinoma (OV), sarcoma (SARC), lung cancer, lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LU AD), stomach cancer, stomach adenocarcinoma (STAD), bladder cancer, bladder urothelial carcinoma (BLCA), esophageal cancer, esophageal carcinoma (ESCA), adrenocortical carcinoma, breast cancer, breast invasive carcinoma (BRCA), pancreatic cancer, pancreatic adenocarcinoma (PAAD), fallopian tube cancer, primary peritoneal cancer liver cancer, liver hepatocellular carcinoma (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), endocervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, skin cutaneous melanoma (SKCM), glioblastoma multiforme (GBM), kidney cancer, or kidney chromophobe (KICH).

109. The method of any one of claims 101-107, wherein the CCNE1 amplified cancer is nonsmall cell lung cancer (NSCLC).

110. The method of any one of claims 101-107, wherein the CCNE1 amplified cancer is ovarian cancer.

111. The method of any one of claims 101-107, wherein the CCNE1 amplified cancer is breast cancer.

112. The method of any one of claims 101-111, wherein an NGS panel test is used to confirm CCNE1 overexpression or amplification status, and wherein the NGS panel test is selected from Foundation One® CDx, Foundation One® Liquid CDx, Tempus xT (solid tumor), Tempus xF (liquid biopsy), Caris® Life Sciences Molecular Profiling, or OncoHelix Solid Tumor NGS.

113. The method of any one of claims 1-112, wherein the method results in tumor necrosis.

114. The method of any one of claims 1-113, wherein INX-315 is administered in a dosage form between about 100 mg and about 800 mg.

115. The method of any one of claims 1-114, wherein INX-315 is administered in a dosage form selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg.

116. The method of any one of claims 1-115, wherein INX-315 is administered at least once a day.

117. The method of any one of claims 1-116, wherein INX-315 is continuously administered for at least 21 days, at least 24 days, at least 28 days, at least 35 days, or more than 35 days.

118. The method of any one of claims 1-117, wherein the patient is a human.

119. A pharmaceutical combination comprising:(i) an effective amount of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof;(ii) an effective amount of a KRAS inhibitor selected from AMG-510 (sotorasib), MRTX-849 (adagrasib), MRTX1133, MRTX-EX185, ARS-3248 (JNJ-74699157), ARS-853, ARS-1620, GDC-6036, RG6330, D-1553, BPI-421286, GH35, BEBT-607, LY3499446, MK- 1084, BI-1701963, BI-2865, BI-2493, LY3537982, GDC-6036 (divarasib), D-1553 (garsorasib), HBI-2438, JDQ443 (opnurasib), JAB-21822, JAB-21000, HS-10370 IBI-351 (GFH925) BI- 1823911, AZD4625, AZD4747, FMC-376, LY3537982 (Olomorasib), garsorasib, Opnurasib, D3S-001, BBO-8956, Fulzerasib (IBI531), ERAS-3490, JDQ443, ELI-002, DCC-3116, BDTX- 4933, RMC-4630, RM-018, RMC-6291, RMC-6236, BI-2852, BI-2493, YL-15293, GEC255, SY- 5933, BBO-8520, RMC-9805, ASP3082, HRS-4642, INCB161731, QTX3046, JAB-22000, VRTX153, ERAS-4, LY3962673, RMC-5127, RMC-0708, RMC-8839, BI3706674, QTX3034, QTX3544, JAB-23425, LY406634, VRTX180, ACB13, or BI-2865, or a pharmaceutically acceptable salt thereof; and(iii) one or more pharmaceutically acceptable excipients.

120. The pharmaceutical combination of claim 119, comprising an amorphous spray-dried dispersion (ASD) of INX-315.

121. The pharmaceutical combination of claim 120, wherein INX-315 is between about 20% and about 60% by weight of the ASD.

122. The pharmaceutical combination of claim 120 or 121, wherein INX-315 is between about 30% and about 50% by weight of the ASD.

123. The pharmaceutical combination of any one of claims 120-122, wherein INX-315 is about 40% by weight of the ASD.

124. The pharmaceutical combination of any one of claims 119-123, in a dosage from selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg of INX-315, or a pharmaceutically acceptable salt thereof.

125. The pharmaceutical combination of any one of claims 120-124, wherein the ASD further comprises a precipitation preventer.

126. The pharmaceutical combination of claim 125, wherein the precipitation preventer is selected from a cellulose derivative, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxy ethyl cellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethyl cellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, PVP K 30, PVP K 25, PVP VA64, or PVP VA37.

127. The pharmaceutical combination of claim 125 or 126, wherein the precipitation preventer is HPMCAS-HG.

128. The pharmaceutical combination of any one of claims 125-127, wherein the precipitation preventer in the ASD is between about 40% and about 80% by weight of the ASD.

129. The pharmaceutical combination of any one of claims 125-128, wherein the precipitation preventer in the ASD is about 60% by weight of the ASD.

130. Use of an effective amount of the pharmaceutical combination of any one of claims 119- 129, in the manufacture of a medicament for delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer.

131. A method for delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer, comprising administering to the patient an effective amount of the pharmaceutical combination of any one of claims 119-129.

132. Use of an effective amount of the pharmaceutical combination of any one of claims 119- 129, in the manufacture of a medicament for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof.

133. A method for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical combination of any one of claims 119-129.

134. A pharmaceutical combination comprising:(i) an effective amount of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof;(ii) an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor selected from RO-3306, CGP-74514A, BEY1107 (avotaciclib), alsterpaullone, kenpaullone, CVT-313, staurosporine, JNJ-7706621, olomoucine, SU9516, CDKi277, bohemine, CYC202, 3-ATA, NU2058, purvalanol A, BMS-265246, flavopiridol (alvocidib), roniciclib (BAY1000394), P276- 00 (riviciclib), dinaciclib (SCH727965), AT7519, seliciclib (roscovitine), AG-024322, PHA- 793887, R547, RGB-286638, AZD-5438, indirubin (couroupitine B), milciclib, PHA-848125AC, or indirubin-5-sulfonic acid, or a pharmaceutically acceptable salt thereof; and(iii) one or more pharmaceutically acceptable excipients.

135. The pharmaceutical combination of claim 134, comprising an amorphous spray-dried dispersion (ASD) of INX-315.

136. The pharmaceutical combination of claim 135, wherein INX-315 is between about 20% and about 60% by weight of the ASD.

137. The pharmaceutical combination of claim 135 or 136, wherein INX-315 is between about 30% and about 50% by weight of the ASD.

138. The pharmaceutical combination of any one of claims 135-137, wherein INX-315 is about 40% by weight of the ASD.

139. The pharmaceutical combination of any one of claims 134-138, in a dosage from selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg of INX-315, or a pharmaceutically acceptable salt thereof.

140. The pharmaceutical combination of any one of claims 135-139, wherein the ASD further comprises a precipitation preventer.

141. The pharmaceutical combination of claim 140, wherein the precipitation preventer is selected from a cellulose derivative, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethyl cellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, PVP K 30, PVP K 25, PVP VA64, or PVP VA37.

142. The pharmaceutical combination of claim 140 or 141, wherein the precipitation preventer is HPMCAS-HG.

143. The pharmaceutical combination of any one of claims 140-142, wherein the precipitation preventer in the ASD is between about 40% and about 80% by weight of the ASD.

144. The pharmaceutical combination of any one of claims 140-143, wherein the precipitation preventer in the ASD is about 60% by weight of the ASD.

145. Use of an effective amount of the pharmaceutical combination of any one of claims 134- 144, in the manufacture of a medicament for treating a patient having a CCNE1 amplified cancer.

146. A method for treating a patient having a CCNE1 amplified cancer, comprising administering to the patient an effective amount of the pharmaceutical combination of any one of claims 134-144.

147. Use of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor for treating a patient having a KRAS mutant cancer.

148. Use of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor in the manufacture of a medicament to treat a patient having a KRAS mutant cancer.

149. Use of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof for delaying acquired resistance to a RAS inhibitor in a patient in need thereof, wherein the patient has already received, will receive administration of, or is receiving the RAS inhibitor.

150. Use of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to delay acquired resistance to a RAS inhibitor in a patient in need thereof, wherein the patient has already received, will receive administration of, or is receiving the RAS inhibitor.

151. Use of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, wherein the patient has already received or is receiving the RAS inhibitor.

152. Use of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to resensitize a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, wherein the patient has already received or is receiving the RAS inhibitor.

153. Use of a CDK2 inhibitor compound of structure:pharmaceutically acceptable salt thereof for treating a patient having a KRAS mutant cancer, comprising:(i) obtaining a sample from the patient;(ii) detecting whether KRAS is mutated in the sample compared with a control sample;(iii) if KRAS comprises a mutation, then administering to the patient:(a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and(b) an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

154. Use of a CDK2 inhibitor compound of structure:in the manufacture of a medicament to treat a patient having a KRAS mutant cancer, comprising:(i) obtaining a sample from the patient;(ii) detecting whether KRAS is mutated in the sample compared with a control sample;(iii) if KRAS comprises a mutation, then administering to the patient:(a) an effective amount of the CDK2 inhibitor compound INX-315,or a pharmaceutically acceptable salt thereof; and(b) an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

155. Use of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof for treating a patient having a KRAS mutant cancer comprising loss of function of p53.

156. Use of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat a patient having a KRAS mutant cancer comprising loss of function of p53.

157. Use of a CDK2 inhibitor compound of structure:pharmaceutically acceptable salt thereof for treating a patient having a KRAS mutant cancer with a p53 loss of function mutation, comprising:(i) obtaining a sample from the patient;(ii) detecting whether the sample has a p53 loss of function mutation compared with a control sample;(iii) if the sample comprises a p53 loss of function mutation, then administering to the patient:(a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof.

158. Use of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat a patient having a KRAS mutant cancer with a p53 loss of function mutation, comprising:(i) obtaining a sample from the patient;(ii) detecting whether the sample has a p53 loss of function mutation compared with a control sample;(iii) if the sample comprises a p53 loss of function mutation, then administering to the patient:(a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof.

159. Use of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor for treating a patient having a CCNE1 amplified cancer.

160. Use of a cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor in the manufacture of a medicament to treat a patient having a CCNE1 amplified cancer.

161. Use of a CDK2 inhibitor compound of structure:pharmaceutically acceptable salt thereof for treating a patient having a CCNE1 amplified cancer, comprising:(i) obtaining a sample from the patient;(ii) detecting whether CCNE1 is amplified or overexpressed in the sample compared with a control sample;(iii) if CCNE1 is amplified or over expressed, then administering to the patient:(a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and(b) an effective amount of a CDK1 inhibitor, or a pharmaceutically acceptable salt thereof.

162. Use of a CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat a patient having a CCNE1 amplified cancer, comprising:(i) obtaining a sample from the patient;(ii) detecting whether CCNE1 is amplified or overexpressed in the sample compared with a control sample;(iii) if CCNE1 is amplified or over expressed, then administering to the patient:(a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and(b) an effective amount of a CDK1 inhibitor, or a pharmaceutically acceptable salt thereof.

163. Use of an effective amount of the pharmaceutical combination of any one of claims 119- 129 for delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer.

164. Use of an effective amount of the pharmaceutical combination of any one of claims 119- 129 for resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof.

165. Use of an effective amount of the pharmaceutical combination of any one of claims 134- 144 for treating a patient having a CCNE1 amplified cancer.

166. A cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, in combination or alternation with an effective amount of a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor for use treating a patient having a KRAS mutant cancer.

167. A CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof for use delaying acquired resistance to a RAS inhibitor in a patient in need thereof, wherein the patient has already received, will receive administration of, or is receiving the RAS inhibitor.

168. A CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof for use resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof, wherein the patient has already received or is receiving the RAS inhibitor.

169. A CDK2 inhibitor compound of structure:pharmaceutically acceptable salt thereof for use treating a patient having a KRAS mutant cancer, comprising:(i) obtaining a sample from the patient;(ii) detecting whether KRAS is mutated in the sample compared with a control sample;(iii) if KRAS comprises a mutation, then administering to the patient:(a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and(b) an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

170. A CDK2 inhibitor compound of structure:or a pharmaceutically acceptable salt thereof for use treating a patient having a KRAS mutant cancer comprising loss of function of p53.

171. A CDK2 inhibitor compound of structure :pharmaceutically acceptable salt thereof for use treating a patient having a KRAS mutant cancer with a p53 loss of function mutation, comprising:(i) obtaining a sample from the patient;(ii) detecting whether the sample has a p53 loss of function mutation compared with a control sample;(iii) if the sample comprises a p53 loss of function mutation, then administering to the patient:(a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof.

172. A cyclin dependent kinase 2 (CDK2) inhibitor compound of structure:or a pharmaceutically acceptable salt thereof, for use in combination or alternation with an effective amount of a cyclin dependent kinase 1 (CDK1) inhibitor for treating a patient having a CCNE1 amplified cancer.

173. A CDK2 inhibitor compound of structure:pharmaceutically acceptable salt thereof for use treating a patient having a CCNE1 amplified cancer, comprising:(i) obtaining a sample from the patient;(ii) detecting whether CCNE1 is amplified or overexpressed in the sample compared with a control sample;(iii) if CCNE1 is amplified or overexpressed, then administering to the patient:(a) an effective amount of the CDK2 inhibitor compound INX-315 or a pharmaceutically acceptable salt thereof; and(b) an effective amount of a CDK1 inhibitor, or a pharmaceutically acceptable salt thereof.

174. A pharmaceutical combination of any one of claims 119-129 for use delaying acquired resistance to a RAS inhibitor in a patient having a KRAS mutant cancer.

175. A pharmaceutical combination of any one of claims 119-129 for use resensitizing a KRAS mutant cancer to a RAS inhibitor in a patient in need thereof.

176. A pharmaceutical combination of any one of claims 134-144 for use treating a patient having a CCNE1 amplified cancer.

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