Application of daptomycin in preparation of non-small cell lung cancer KRAS G12C inhibitor drug resistance reversal agent

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of daptomycin in preparation of a non-small cell lung cancer KRAS G12C inhibitor drug resistance reversal agent. It is found that the problem of drug resistance of non-small cell lung cancer to a KRAS inhibitor can be solved through combination of daptomycin and adagraxib, an excellent anti-tumor effect is shown, the drug resistance phenotype mediated by an acquired drug resistance mechanism can be remarkably reversed, no obvious toxic or side effect is observed in an experimental animal body, and the safety characteristic is good. In order to overcome the problem of drug resistance of targeted drugs such as KRAS inhibitors, the invention provides a novel combined treatment solution with high efficiency and safety.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological medicine, and particularly relates to application of daptomycin in preparation of a non-small cell lung cancer KRAS G12C inhibitor resistance reversing agent. BACKGROUND

[0002] Non-small cell lung cancer (NSCLC) is one of the most burdensome malignant tumors in the world. Global cancer statistics in 2022 show that there are about 2.47 million new cases of lung cancer and about 1.81 million deaths, with the incidence and mortality rates ranking first among all cancers. From the perspective of pathology, lung cancer is mainly divided into two categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which NSCLC accounts for about 85% of the total number of lung cancer. Although significant progress has been made in the diagnosis and treatment of NSCLC in recent years, the overall 5-year survival rate is still only about 21.7%. Given its high incidence and mortality, exploring more effective diagnosis and treatment strategies has great public health value and medical significance. The treatment strategy for NSCLC is mainly formulated according to the disease stage. Early patients are mainly treated by surgical resection, supplemented by radiotherapy or chemotherapy. Advanced patients mainly rely on systemic treatment, including chemotherapy, targeted therapy, immunotherapy and combined strategies of the above methods. Among them, targeted therapy is an important progress in recent years. About 70% of NSCLC patients carry targetable driver gene mutations, and KRAS gene is one of the important mutation types. Targeted drugs significantly improve treatment efficiency and reduce the toxicity of traditional chemotherapy by specifically inhibiting key molecules in oncogenic signaling pathways, and have become the core treatment for advanced NSCLC, significantly improving the survival rate and quality of life of patients.

[0003] KRAS gene is one of the common driver gene mutations in malignant tumors, with the highest mutation frequency in pancreatic cancer, colorectal cancer and lung adenocarcinoma. KRAS mutations mostly occur in codon 12, but the distribution in different cancers is different: in pancreatic cancer and colorectal cancer, the most common mutation type is KRAS G12D, followed by G12V; while in lung adenocarcinoma, KRAS G12C is the main mutant subtype, accounting for about 14% of all lung adenocarcinoma cases. Due to the relatively smooth surface of KRAS protein, lacking of "pocket" for traditional drugs to easily bind, it has been regarded as an "undruggable" target for a long time. Adagrasib, developed by Mirati Therapeutics, is an oral small molecule inhibitor that can selectively and covalently bind to the cysteine residue of KRAS G12C mutant protein, locking it in an inactive state, thereby effectively blocking downstream MAPK and PI3K signaling pathways and inhibiting tumor cell proliferation and survival. Its selectivity for mutant KRAS is much higher than that for wild-type, which helps to reduce off-target toxicity. Currently, Adagrasib is the only drug approved by the US FDA for marketing, and it is used to treat advanced NSCLC and colorectal cancer carrying KRAS G12C mutation.

[0004] Daptomycin is a cyclic lipopeptide antibiotic. Daptomycin mainly acts on the cell membrane of gram-positive bacteria. Activated daptomycin interacts with negatively charged phospholipids to form an "ion channel" like structure on the cell membrane, causing ions to flow out of the cell, rapid depolarization of the cell membrane, inhibition of synthesis of RNA, DNA and large molecular proteins, leading to bacterial death. Clinically, daptomycin has good clinical application value in the treatment of bacteremia, complex skin and soft tissue infections, infective endocarditis, etc. due to its characteristics of being able to penetrate biofilm and not causing bacterial lysis, thereby avoiding the release of inflammatory mediators from the bacterial content and triggering severe inflammatory reactions.

[0005] It is reported that the median overall survival of the only marketed KRAS inhibitor Adagrasib is about 12.6 months, and the median progression-free survival is about 6.5 months. The biggest problem in clinical practice is that many patients show significant clinical effects initially, but soon relapse or tumor resistance increases. The resistance mechanisms can be divided into two categories: (1) KRAS-dependent resistance: secondary mutation of KRAS, KRAS amplification; (2) Non-KRAS-dependent resistance: abnormal upstream signals, downstream effector molecule mutations, alternative activation of bypass pathways, and histological transformation. However, about 55% of drug-resistant patients do not have a clear driving mechanism.

[0006] Therefore, in view of the serious drug resistance problem, the current clinical treatment mode is to use combined drugs to reverse drug resistance, such as combined with EGFR inhibitors, combined with SHP2 inhibitors, combined with immunotherapy, etc. However, most of them are still in the clinical research stage, and there are problems such as large toxic and side effects, short duration of efficacy, and significant heterogeneity of efficacy. Therefore, new combined treatment methods are urgently needed to solve the drug resistance problem of adagrasib. SUMMARY

[0007] The first aspect of the present application aims to provide the use of daptomycin in the preparation of a medicament for treating KRAS inhibitor-resistant tumors.

[0008] The second aspect of the present application aims to provide the use of daptomycin and KRAS inhibitors in the preparation of a medicament for treating tumors.

[0009] The third aspect of the present application aims to provide a pharmaceutical composition.

[0010] In order to achieve the above-mentioned purposes of the present application, the technical scheme adopted by the present application is: The first aspect of the present application provides the use of daptomycin in the preparation of a medicament for treating KRAS inhibitor-resistant tumors.

[0011] In some embodiments of the present application, the KRAS inhibitor includes an inhibitor against KRAS gene mutation or a broad-spectrum KRAS inhibitor.

[0012] In some embodiments of the present application, the broad-spectrum KRAS inhibitor includes: RMC-6236, PF-07985045, LY4066434, QTX3544, QTX3034.

[0013] In some embodiments of the present application, the KRAS gene mutation includes KRAS G12C, KRAS G12D, KRAS G12V.

[0014] In some embodiments of the present application, the inhibitor against KRAS G12C gene mutation includes: Sotorasib, Adagrasib, Fulzerasib, Garsorasib, Glecirasib.

[0015] In some embodiments of the present application, the inhibitor against KRAS G12D gene mutation includes: MRTX1133, HRS-4642, AZD0022, LY3962673.

[0016] In some embodiments of the application, the inhibitor against KRAS G12V gene mutation comprises: AFNT-211, NW-301V, CRTKVA11.

[0017] In some embodiments of the application, the KRAS inhibitor comprises adagrasyl.

[0018] In some embodiments of the application, the tumor comprises non-small cell lung cancer.

[0019] In some embodiments of the application, the daptomycin has the following structural formula: .

[0020] In some embodiments of the application, the daptomycin comprises a pharmaceutically acceptable salt thereof.

[0021] In some embodiments of the application, the pharmaceutically acceptable salt comprises an acid addition salt and a base addition salt.

[0022] “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and an organic acid such as, but not limited to, acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor 10 sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfic acid, ethane 1,2 disulfonic acid, ethanesulfonic acid, 2 hydroxyethanesulfonic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2 oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, and the like, which retains the biological effectiveness and properties of the free base and is not biologically or otherwise undesirable.

[0023] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared from addition of inorganic or organic acids to the free base. Salts derived from inorganic acids include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic acids include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0024] In some embodiments of the present application, the medicament comprises a pharmaceutically acceptable excipient.

[0025] In some embodiments of the present application, the pharmaceutically acceptable excipient comprises at least one of a propellant, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure adjusting agent, a stabilizer, a glidant, a flavoring agent, a preservative, a suspending agent, a coating material, a fragrance, an anti-adherent, a penetration enhancer, a pH adjusting agent, a buffer, a plasticizer, a surfactant, a foaming agent, an antifoaming agent, a thickening agent, an inclusion agent, a humectant, an absorbent, a diluent, a flocculating agent and a deflocculating agent, a filter aid, a release retarder.

[0026] The above pharmaceutically acceptable excipients are generally recognized as suitable for this use in the art and are non-active ingredients of the medicament. A compendium of pharmaceutically acceptable excipients can be found in the Handbook of Pharmaceutical Excipients, 2ndEdition, Edited by A. Wade and P. J. Weller; published by American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994; the Compendium of Chinese Pharmacopoeia-Pharmaceutical Excipients, and the like.

[0027] In some embodiments of the present application, the dosage form of the product comprises one of a powder, a tablet, a granule, a capsule, a sustained release, a solution, a dry suspension, an effervescent tablet, an emulsion, a suspension, a syrup, a drop, a chewable tablet.

[0028] In some embodiments of the present application, the administration of the product comprises gastrointestinal administration or non-gastrointestinal administration.

[0029] In some embodiments of the present application, the gastrointestinal administration comprises one of oral administration, sublingual administration, rectal administration.

[0030] In some embodiments of the present application, the non-gastrointestinal administration comprises one of intravenous injection, subcutaneous injection, mucosal administration.

[0031] In some embodiments of the present application, the subject of the administration of the product is a mammal; including but not limited to: human, mouse, rat, pig, cow, sheep, horse, monkey, rabbit.

[0032] In some embodiments of the present application, the mammal includes human.

[0033] In a second aspect of the present application, there is provided a use of daptomycin and a KRAS inhibitor in the preparation of a medicament for treating a tumor.

[0034] In some embodiments of the present application, the KRAS inhibitor comprises an inhibitor against KRAS gene mutation or a broad-spectrum KRAS inhibitor.

[0035] In some embodiments of the present application, the tumor comprises non-small cell lung cancer.

[0036] In some embodiments of the present application, the daptomycin comprises a pharmaceutically acceptable salt thereof.

[0037] In some embodiments of the present application, the medicament comprises a pharmaceutically acceptable excipient.

[0038] In a third aspect of the present application, there is provided a pharmaceutical composition comprising daptomycin and a KRAS inhibitor.

[0039] In some embodiments of the present application, the KRAS inhibitor comprises an inhibitor against KRAS gene mutation or a broad-spectrum KRAS inhibitor.

[0040] In some embodiments of the present application, the KRAS inhibitor comprises adagrasyl.

[0041] In some embodiments of the present application, the daptomycin comprises a pharmaceutically acceptable salt thereof.

[0042] In some embodiments of the present application, the medicament comprises a pharmaceutically acceptable excipient.

[0043] The beneficial effects of the present application are: KRAS inhibitors such as adagrasib face a serious drug resistance problem in the treatment of non-small cell lung cancer, about 55% of patients have unknown drug resistance mechanism. The present application first discloses that daptomycin can effectively reverse this drug resistance: in vitro experiments, the combination of daptomycin and adagrasib significantly reduces the IC 50 value of drug-resistant Calu1 AR cells from 2.839 μM of single drug to 0.757 μM (decrease by 73.3%), with a HSA synergy score of 14.097, confirming a strong synergistic effect. Through clonogenic assay and combination index analysis (CI<0.3), it is further proved that this synergistic effect covers the primary drug-resistant H2030 cells. In the nude mouse subcutaneous tumor model, the tumor volume of the combination group is reduced by >60% compared with the single drug group, the tumor weight is significantly reduced, and no drug resistance recurrence occurs within the 22-day treatment period, while the mouse body weight is stable, indicating good safety and important clinical value. The present application overcomes the drug resistance problem of KRAS inhibitors and other targeted drugs, and provides a new combined treatment solution with high efficiency and safety. BRIEF DESCRIPTION OF DRAWINGS

[0044] The present application will be further described below in conjunction with the drawings and examples, in which: Figure 1 The effects of daptomycin alone and in combination with adagrasib on the viability of adagrasib-resistant cells are shown in the following table, where: A is the IC 50 value of Calu1 cells treated with adagrasib alone detected by MTT (thiazolyl blue) method; B is the IC 50 value of Calu1 parental (PR) and adagrasib-resistant (AR) cells detected by MTT method; C is the IC 50 value of Calu1 AR and H2030 cells treated with daptomycin alone; D is the IC 50 value of Calu1 AR cells treated with daptomycin (4 μM) and adagrasib in combination.

[0045] Figure 2 The effects of daptomycin alone, adagrasib alone, and the combination of the two drugs on the proliferation ability of adagrasib-resistant Calu1 AR (A) and H2030 (B) cells are shown in the following table.

[0046] Figure 3 The results of evaluating the combined inhibition effect of daptomycin and adagrasib in Calu1 AR and H2030 cells by Synergy Finder 3.0 tool are shown in the following table, where: A and C are inhibition rate matrix heat maps of the two drugs at different concentration combinations; B and D are the quantitative scores of the synergistic effect using the HSA model.

[0047] Figure 4 The synergistic effect of the combination of daptomycin and adagrasib was quantitatively evaluated by calculating the combination index (CI), wherein A is the Calu1 AR cell result; and B is the H2030 cell result.

[0048] Figure 5 The in vivo pharmacodynamic evaluation results of the combination of daptomycin and adagrasib are shown in the following table A is the tumor real photo of Calu1 AR tumor-bearing mice in the control group, the daptomycin monotherapy group, the adagrasib monotherapy group and the combination therapy group at the end of the experiment; B is the dynamic growth curve of tumor volume; C is the tumor weight statistical result at the end of the experiment; and D is the body weight change curve of nude mice during the treatment process. DETAILED DESCRIPTION

[0049] The concept and technical effects of the present application will be described below in conjunction with examples for a clear and complete description, so as to fully understand the purpose, features and effects of the present application. Obviously, the described examples are only a part of the examples of the present application, but not all the examples. Based on the examples of the present application, other examples obtained by those skilled in the art without creative labor are within the protection scope of the present application.

[0050] Example 1 Construction of adagrasib acquired resistant strain, The Calu1AR (Adagrasib Resistance, AR) cell strain with acquired resistance to adagrasib was constructed by using the concentration gradient increasing method for 4 months, and the IC 50 was detected by MTT experiment.

[0051] 1. Experimental method MTT experimental method: Calu1 AR cells in logarithmic growth phase were taken and inoculated in 96-well plates (4000 / well), and after 12 h of cell adhesion, the drug medium was replaced. The cells were continuously cultured under drug treatment for 72 h. 20 μl of MTT (5 mg / ml) was added to each well for 6 h of incubation, after which the medium was removed and 150 μl of DMSO was added to each well. The precipitate was fully dissolved using a shaker. The OD value at 490 nm was determined using an enzyme-labeled instrument. The data was exported and the cell survival rate (%) of each group was calculated as follows: (experimental group OD value-blank well OD value) / (control group OD value-blank well OD value) x 100%. Calu1 and H2030 cells were purchased from the American type culture collection (ATCC). The above cells have been identified by STR (Short Tandem Repeat) of the Forensic Identification Center of Sun Yat-sen University, and the standard product is consistent, ensuring the reliability of the cells. Daptomycin and adagrasyl were purchased from KKL company.

[0052] 2. Experimental results Results Figure 1 As shown in Table A, the present application selects KRAS G12C mutant cell lines Calu1 and H2030, and MTT experiments show that Calu1 is sensitive to adagrasyl IC 50 about 0.1129 μM, and H2030 is 4.189 μM. Calu1 is defined as an adagrasyl sensitive strain, and H2030 is defined as an adagrasyl primary drug-resistant strain.

[0053] Results Figure 1 As shown in Table B, the IC 50 value of adagrasyl-treated Calu1 AR cells is 2.839 μM, and the drug resistance index is >10, which meets the standard of acquired drug resistance. Results Figure 1 As shown in Table C, after 4 μM daptomycin treatment of Calu1 AR and H2030 cells, the cell survival rates are both >80%, indicating that this concentration only produces slight inhibition of cell proliferation and is suitable for subsequent combination experiments. As shown in Table 1D, after adagrasyl combined with 4 μM daptomycin treatment, the IC 50 of Calu1 AR cells is significantly reduced to 0.757 μM (73.3% lower than adagrasyl alone), confirming that the combination of the two drugs has a significant synergistic effect.

[0054] Example 2 Through plate colony formation experiments, the inhibitory effects of daptomycin, adagrasyl and their combination on the proliferation of adagrasyl acquired drug-resistant cells (Calu1 AR) and primary drug-resistant cells (H2030) were systematically evaluated to verify the synergistic effect of the two drugs.

[0055] 1. Experimental method Logarithmic growth phase cells Calu1 AR and H2030 were taken and inoculated in 12-well plates (1000 / well), and after 24 h of cell adhesion, the drug culture medium was replaced. The following four groups were set: ① control group: complete culture medium containing solvent (DMSO, concentration matched with treatment group); ② daptomycin single-drug group: 4 μM daptomycin treatment; ③ adagrasyl group: 2 μM adagrasyl treatment; ④ combined drug group: 4 μM daptomycin + 2 μM adagrasyl co-treatment. Continuous culture for 10-14 days (drug-containing medium was replaced every 3 days), until the control group formed visible cell clones. After discarding the culture medium, methanol was used for fixation for 15 minutes, and 1% crystal violet staining was performed overnight at room temperature. The residual dye was removed by flowing water and dried at room temperature. A high-definition scanner was used to record the clone formation of each well.

[0056] 2. Experimental results Results Figure 2 As shown in the figure, when daptomycin and adagrasyl were used in combination to treat Calu1 AR and H2030 cells, both groups showed significant synergistic effect, and the number of clone formation was significantly reduced compared with the control group and the single-drug group.

[0057] Example 3 Cell proliferation was detected by MTT experiment, and the synergistic effect of daptomycin and adagrasyl was quantitatively analyzed using Synergy Finder 3.0 website.

[0058] 1. Experimental method Logarithmic growth phase cells Calu1 AR and H2030 were taken and inoculated in 96-well plates (4000 / well), and after 12 h of cell adhesion, the drug culture medium was replaced. The cells were cultured for 72 h in the drug matrix concentration. 20 μl MTT (5 mg / ml) was added to each well and incubated for 6 h, and after the culture medium was removed, 150 μL DMSO was added to each well, and the precipitate was fully dissolved using a shaker. The OD value of each well was measured by a microplate reader at an excitation wavelength of 490 nm. The data was exported, and the cell survival rate (%) = (experimental group OD value-blank well OD value) / (control group OD value-blank well OD value) x 100% was calculated. The cell survival rate data was imported into Synergy Finder 3.0 (website: https: / / synergyfinder.fimm.fi) according to the Excel format of Synergy Finder 3.0 software, and the website generated a heat map, synergy effect index, etc. The Synergy Finder synergy score mode selected the HSA model, and the scoring standard was: Score>10 for significant synergy, 0-10 for additive effect, and <0 for antagonism.

[0059] 2. Experimental results Results Figure 3 As shown in Calu1 AR (A) and H2030 (C) cells, daptomycin combined with adagrasyl significantly enhanced the inhibition of cell proliferation compared with single drug treatment. Figure 3 As shown in Calu1 AR (A) and H2030 (C) cells, daptomycin combined with adagrasyl significantly enhanced the inhibition of cell proliferation compared with single drug treatment.

[0060] Example 4 Cell proliferation was detected by MTT experiment, and the combination index CI was calculated by CompuSyn program to quantitatively evaluate the synergistic effect of daptomycin combined with adagrasyl.

[0061] 1. Experimental method Experimental method: Calu1 AR and H2030 cells in logarithmic growth phase were taken and inoculated in 96-well plates (4000 / well), and the drug medium was replaced after 12 h of cell adhesion. The cells were cultured with drug combination for 72 h. 20 μL MTT (5 mg / ml) was added to each well for 6 h, and then the medium was removed and 150 μL DMSO was added to each well. The precipitate was fully dissolved using a shaker. The OD value of each well was measured by a microplate reader at an excitation wavelength of 490 nm. The data was exported and the cell survival rate (%) was calculated = (experimental group OD value-blank well OD value) / (control group OD value-blank well OD value) x 100%. The combination index CI was calculated by using CompuSyn software. CI value > 1 indicates that the drug combination has antagonistic effect, 0.7 < CI < 1 indicates that the drug combination has weak synergistic or additive effect, 0.3 < CI < 0.7 indicates that the drug combination has synergistic effect, and CI < 0.3 indicates that the drug combination has strong synergistic effect.

[0062] 2. Experimental results Results Figure 4 As shown in Calu1 AR (A) and H2030 (C) cells, daptomycin combined with adagrasyl significantly enhanced the inhibition of cell proliferation compared with single drug treatment.

[0063] Example 5 The synergistic effect of daptomycin combined with adagrasyl on anti-tumor was evaluated in vivo by subcutaneous tumor formation experiment in nude mice.

[0064] Twenty female Balb / c-nu mice were purchased from Guangdong Yaokang Biotechnology Co., Ltd. All mice were housed under specific pathogen-free conditions, and the experimental protocol was approved by the Animal Welfare and Care Committee of Sun Yat-sen University. Mice were randomly grouped according to age and weight, and were 4-6 weeks old at the time of injection. Matrigel was purchased from Corning Institution.

[0065] 1. Experimental Methods Calu1 AR cells were resuspended in PBS and the cell density was adjusted to 3 × 10⁻⁶. 7 Cells / mL: 100 μl of cell suspension was mixed with 100 μL of Matrigel and subcutaneously injected into the groin of mice. Mice were divided into 4 groups (n=5 per group): (1) Control group (solvent treatment); (2) Daptomycin monotherapy group (10 mg / kg); (3) Adaggrasibu monotherapy group (10 mg / kg); (4) Daptomycin and adagrasib combination therapy (10 mg / kg each).

[0066] Drug administration began on day 10 post-inoculation (at which time the tumor volume was approximately 100 mm³). Daptomycin was administered intravenously, and adagraxib was administered by gavage, every 2 days. Tumor volume was measured regularly, and mouse weight was recorded. The experiment was terminated when the tumor volume approached the ethical endpoint; mice were euthanized, and subcutaneous tumor tissue was harvested for imaging and weighing.

[0067] 2. Experimental Results The results are as follows Figure 5 As shown in Figures A, B, and C: In Calu1 AR tumor-bearing mice, compared to the control group, adagrasibu monotherapy initially inhibited tumor growth (reduced tumor volume and weight), but resistance gradually developed later, and tumor growth resumed. In contrast, the combination therapy group showed a significant reduction in tumor volume and weight compared to adagrasibu monotherapy, and no resistance was observed during the 22-day treatment period. Figure 5 The results showed that neither adagrasibu monotherapy nor combination therapy caused significant changes in mouse body weight, suggesting that the drug did not exhibit significant toxicity at the tested doses.

[0068] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments, and various changes can be made within the scope of knowledge possessed by those skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. Application of daptomycin in the preparation of drugs for treating KRAS inhibitor-resistant tumors.

2. The application according to claim 1, characterized in that: The KRAS inhibitors include inhibitors targeting KRAS gene mutations or broad-spectrum KRAS inhibitors. The KRAS gene mutations include KRAS G12C, KRAS G12D, and KRAS G12V.

3. The application according to claim 2, characterized in that: The KRAS inhibitors include adagrasibu.

4. The application according to claim 1, characterized in that: The tumors include non-small cell lung cancer.

5. The application according to claim 1, characterized in that: The daptomycin includes its pharmaceutically acceptable salts.

6. The application according to claim 1, characterized in that: The drug includes pharmaceutically acceptable excipients.

7. The application according to claim 1, characterized in that: The dosage forms of the drug include those administered via the gastrointestinal tract or those administered outside the gastrointestinal tract.

8. The application according to claim 1, characterized in that: The drug is administered to mammals.

9. Application of daptomycin and KRAS inhibitors in the preparation of drugs for treating tumors.

10. A pharmaceutical composition, characterized in that: The pharmaceutical composition includes daptomycin and a KRAS inhibitor; Preferably, the KRAS inhibitor comprises adagracib.

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