Application of ferroptosis inhibitor combined with KRAS inhibitor in the preparation of drugs for treating KRAS mutant tumors and pharmaceutical composition

Abstract

This invention provides the application and pharmaceutical composition of ferroptosis inhibitors in combination with KRAS inhibitors in the preparation of drugs for treating KRAS-mutant tumors, relating to the field of biomedical technology. This application combines ferroptosis inhibitors and KRAS inhibitors; compared to using either ferroptosis inhibitor or KRAS inhibitor alone, the combined use significantly inhibits tumor cell proliferation and exhibits a significant synergistic effect against KRAS-mutant tumors. Therefore, ferroptosis inhibitors and KRAS inhibitors can be used either in combination or formulated into a combination preparation for the treatment of KRAS-mutant tumors.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to an application of a ferroptosis inhibitor combined with a KRAS inhibitor in preparing a drug for treating KRAS mutant tumors and a pharmaceutical composition. Background Art

[0002] At present, mutations in the oncogene RAS (HRAS, NRAS, KRAS) cause about one-third of human cancers, especially KRAS mutations, which often lead to fatal malignancies, including pancreatic cancer (91%), colon cancer (42%) and lung cancer (33%), and are associated with poor prognosis. Unfortunately, the benefits of targeted therapy for KRAS mutant tumors are very limited. Since it is very difficult to directly inhibit KRAS protein through drugs, there is still a lack of approved drugs targeting KRAS in clinical practice. So far, only two inhibitors targeting KRAS G12C: Sotorasib AMG510 (Sotorasib) and Adagrasib Krazati (Adagrasib) have been approved for the clinical treatment of KRAS G12C mutations in patients with previously treated non-small cell lung cancer. Although the emergence of this drug is a major breakthrough in the clinical application of KRAS inhibitors, only patients with the above-mentioned specific mutations can benefit from it (among which, the above-mentioned specific mutations are most common in non-small cell lung cancer, accounting for about 14%; colorectal cancer accounts for about 3-4%; pancreatic cancer accounts for about 2%). In addition, the feedback activation of KRAS upstream signal EGFR and downstream signaling pathways RAF-MEK-ERK and PI3K-AKT-mTOR will lead to resistance to targeted therapy and limit its clinical application. Therefore, exploring a new combined targeted therapy strategy suitable for KRAS mutant tumors is the current research focus.

[0003] Ferroptosis is an iron-dependent, regulated cell necrosis caused by imbalance of cell membrane lipid peroxidation, with a large accumulation of lipid peroxides as a key downstream feature. Iron accumulation, increased fatty acid supply (especially polyunsaturated fatty acids) and accumulation of lipid peroxides are the key to inducing ferroptosis. Mutations in tumor suppressor genes or oncogenes can lead to tumor metabolic remodeling, including enhanced iron metabolism, increased synthesis of polyunsaturated fatty acids, and inhibition of the ferroptosis defense system. Therefore, the basal ferroptosis signal of the tumor is active and more sensitive to ferroptosis, and inducing ferroptosis has become a new strategy for anti-tumor treatment. However, considering the two sides of things, it is still unclear whether highly active ferroptosis signals have a positive significance for tumor survival. Studies have confirmed that ferroptosis plays a certain positive role in the occurrence and development of tumors. For example, a large amount of oxidized phospholipids produced during tumor cell ferroptosis can inhibit the maturation of antigen-presenting cells DC and the differentiation of helper T cells Th17. In tumor cells with highly active lipid peroxidation, the secretion of prostaglandin E2 (PGE2) increases. PGE2 is an important immunosuppressive factor in the tumor microenvironment, which can directly inhibit the activity of CD8+T cells and NK cells and inhibit DC infiltration into tumors. During the ferroptosis of pancreatic cancer cells, KRAS G12D protein is directly delivered to tumor-associated macrophages TAM through the exosome pathway, promoting their M2 transformation and producing immunosuppressive function. Ferroptotic tumor cells release 8-OHG, which activates the STING-mediated DNA sensor pathway in macrophages, induces the formation of an inflammatory tumor microenvironment, and promotes the formation of pancreatic cancer. This shows that active ferroptosis signals may have a positive effect on tumor survival, and inhibiting tumor ferroptosis signals is a potential anti-tumor strategy.

[0004] To date, no studies have investigated the combined use of ferroptosis inhibitors and KRAS inhibitors for the treatment of KRAS mutant tumors. Summary of the invention

[0005] The purpose of the present invention is to provide a use of a ferroptosis inhibitor combined with a KRAS inhibitor for preparing a drug for treating KRAS mutant tumors and a pharmaceutical composition. The preferred technical solutions among the many technical solutions provided by the present invention can produce many technical effects as described below.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] In a first aspect, the present invention provides an application of a ferroptosis inhibitor combined with a KRAS inhibitor for preparing a drug for treating KRAS mutant tumors, wherein the ferroptosis inhibitor includes one or more of UAMC-3203 or Liproxstatin-1, and the KRAS inhibitor includes one or more of Deltarasin and BAY-293.

[0008] According to a preferred embodiment, the molar ratio of the ferroptosis inhibitor to the KRAS inhibitor in the drug is: 1:(0.17~1.5).

[0009] According to a preferred embodiment, the ferroptosis inhibitor in the drug is UAMC-3203, and the structural formula of UAMC-3203 is: , the KRAS inhibitor includes one of Deltarasin or BAY-293, wherein the structural formula of Deltarasin is , the structural formula of BAY-293 is The molar ratio of the UAMC-3203 to the Deltarasin is 1:(1-0.5), and the molar ratio of the UAMC-3203 to the BAY-293 is 1:(1-0.5).

[0010] In a second aspect, the present application also provides a pharmaceutical composition for treating KRAS mutant tumors, the pharmaceutical composition comprising a ferroptosis inhibitor and a KRAS inhibitor, wherein the ferroptosis inhibitor comprises one or more of UAMC-3203 or Liproxstatin-1, and the KRAS inhibitor comprises one or more of Deltarasin and BAY-293, and the molar ratio of the ferroptosis inhibitor to the KRAS inhibitor in the drug is: 1:(0.17~1.5).

[0011] According to a preferred embodiment, the ferroptosis inhibitor in the pharmaceutical composition is UAMC-3203, and the structural formula of UAMC-3203 is: , the KRAS inhibitor includes one of Deltarasin or BAY-293, wherein the structural formula of Deltarasin is , the structural formula of BAY-293 is The molar ratio of the UAMC-3203 to the Deltarasin is 1:(1-0.5), and the molar ratio of the UAMC-3203 to the BAY-293 is 1:(1-0.5).

[0012] Based on the above technical solution, the application of a ferroptosis inhibitor combined with a KRAS inhibitor for preparing a drug for treating KRAS mutant tumors and a pharmaceutical composition provided in the present application have at least the following beneficial technical effects:

[0013] In the application of the ferroptosis inhibitor combined with the KRAS inhibitor for the preparation of a drug for treating KRAS mutant tumors, the ferroptosis inhibitor and the KRAS inhibitor are used in combination. Compared with the use of the ferroptosis inhibitor or the KRAS inhibitor alone, the combined use of the two can significantly promote tumor cell apoptosis and has a significant synergistic effect against KRAS mutant tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0015] Figure 1 Schematic diagram of UAMC / Lip-1's anti-tumor effect in in vitro experiments. Figure 1 A is the CCK8 cell proliferation results of various types of tumor cells in UAMC / Lip-1 in different experimental drug groups. Figure 1 B is a colony formation experiment diagram of cervical cancer cell HeLa, liver cancer cell PLC / PRF / 5, and colon cancer cell SW480 in different experimental drug groups; Figure 1 C is a schematic diagram of apoptosis detection of cervical cancer cell HeLa, liver cancer cell PLC / PRF / 5, and colon cancer cell SW480 in different experimental drug groups.

[0016] Figure 2 Schematic diagram of the anti-tumor effect of UAMC, a ferroptosis inhibitor, in in vivo experiments. Figure 2 A is a schematic diagram showing that the ferroptosis inhibitor UAMC inhibits the growth of primary liver cancer in mice; Figure 2 B is a schematic diagram of the ferroptosis inhibitor UAMC inhibiting the growth of primary colon cancer in mice.

[0017] Figure 3 This is a schematic diagram of the screening of the new combination of ferroptosis inhibitors and KRAS inhibitors.

[0018] Figure 4 This is a graph showing the synergistic score effect of ferroptosis inhibitors combined with KRAS inhibitors.

[0019] Figure 5 This is a colony formation experiment diagram of ferroptosis inhibitor combined with KRAS inhibitor. DETAILED DESCRIPTION

[0020] To make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0021] The present application provides an application of a ferroptosis inhibitor combined with a KRAS inhibitor for preparing a drug for treating KRAS mutant tumors, wherein the ferroptosis inhibitor in the drug is selected from one or more of UAMC-3203 or Liproxstatin-1, and the KRAS inhibitor is selected from one or more of Deltarasin and BAY-293, and the molar ratio of the ferroptosis inhibitor to the KRAS inhibitor in the drug is: 1:(0.17~1.5).

[0022] Preferably, the ferroptosis inhibitor in the drug is UAMC-3203, and the structural formula of UAMC-3203 is: The KRAS inhibitor is selected from one of Deltarasin and BAY-293, wherein the structural formula of Deltarasin is , the structural formula of BAY-293 is , the molar ratio of UAMC-3203 to Deltarasin is 1:(1~0.5), and the molar ratio of UAMC-3203 to BAY-293 is 1:(1~0.5).

[0023] Preferably, the molar ratio of UAMC-3203 to Deltarasin is 1:0.25 or 1:0.5 or 1:1. Preferably, the molar ratio of UAMC-3203 to BAY-293 is 1:0.25 or 1:0.5 or 1:1.

[0024] The technical solution of the present application is described in detail below in conjunction with specific experiments.

[0025] 1. The tumor cells and drugs involved in the experiment of the present invention are as follows:

[0026] (1) Drugs: DMEM culture medium and fetal bovine serum were purchased from Gibco, USA; trypsin and PBS were prepared in the laboratory; CCK8 was purchased from Shanghai Taoshu Biotechnology Co., Ltd.; Annexin V / PI apoptosis kit was purchased from ABclonal, China; UAMC-3203, Liproxstatin-1, and Deltarasin were purchased from Selleck, USA; Erlotinib, BAY-293, Sorafenib, Dabrafenib, Trametinib, SCH772984, and AZD-5363 were purchased from Shanghai Taoshu Biotechnology Co., Ltd.; Apc Min / + Mice were purchased from Jicui Pharmaceutical Co., Ltd., China; C57BL / 6 mice were purchased from Weitonglihua, China.

[0027] (2) Tumor cells: liver cancer cells PLC / PRF / 5, Huh7, Hep1-6 (mouse origin); colon cancer cells SW480, HCT116, MC38 (mouse origin); cervical cancer cells HeLa; breast cancer cells MDA-MB-231; malignant melanoma cells A375. All of the above are from laboratory preserved cell lines.

[0028] 2. Clarify the anti-tumor effect of ferroptosis inhibitors in in vitro experiments.

[0029] 2.1 Cell culture

[0030] The cells used in the experiment were cultured in a constant temperature incubator at 37°C and 5% CO2 using DMEM medium containing 10% fetal bovine serum. The cells were passaged when they grew to 70-80% fusion.

[0031] 2.2 CCK8 cell proliferation assay.

[0032] Hepatoma cells PLC / PRF / 5, Huh7, Hep1-6 (mouse), colon cancer cells SW480, HCT116, MC38 (mouse), cervical cancer cells HeLa, breast cancer cells MDA-MB-231, and malignant melanoma cells A375 in logarithmic growth phase were seeded in 96-well plates at a density of 3000-7000 cells / well, with 3 replicates per treatment group. Cultured overnight at 37°C, 5% CO2. After cell attachment, the above tumor cells were treated with increasing concentrations of UAMC-3203 (UAMC) (2.5-30μM) or Liproxstatin-1 (Lip-1) (5-40μM) for 48 hours. After treatment, the culture medium was replaced with 100ul CCK8 mixed solution (CCK8 stock solution: serum-free DMEM = 1:10) and cultured in a 37°C incubator for 1-4h. Then, the absorbance OD value (450nm) was measured with an ELISA instrument, the cell viability was detected by CCK8 assay, and the dose-response curve was fitted with GraphPad Prism software to calculate IC50. Cell viability = (OD value of experimental group - average OD value of blank group) / (average OD value of control group - average OD value of blank group) × 100%. The experiment was repeated 3 times and statistical analysis was performed.

[0033] Experimental groups:

[0034] ①Control group: treated with DMSO;

[0035] ② Experimental group: UAMC or Lip-1 treatment;

[0036] ③Blank group: blank wells without cells were added with 100ul serum-free DMEM before measuring the absorbance.

[0037] The volume of drug added to the control group and the experimental group (4 μL / mL culture medium) was the same.

[0038] 2.3 Colony formation assay.

[0039] Cervical cancer cells HeLa, liver cancer cells PLC / PRF / 5, and colon cancer cells SW480 in the logarithmic growth phase were inoculated in a 35 mm culture dish at a density of 1000-3000 cells / well and cultured overnight under conventional conditions. After the cells adhered to the wall, the tumor cells were treated with increasing concentrations of UAMC (0-10μM) and Lip-1 (0-25μM) for 7 days. After the treatment, the cells were washed 3 times with PBS and the residual liquid was aspirated. They were fixed with 4% paraformaldehyde 1mL / dish for 15 minutes, and then stained with 0.5% crystal violet stain for 15 minutes. The residual stain was removed by washing with PBS, dried at room temperature, and the images were taken under bright light.

[0040] 2.4 Flow cytometry was used to detect cell apoptosis.

[0041] The experiment was carried out according to the instructions of the Annexin V / PI double staining apoptosis detection kit. The specific steps are as follows: Cervical cancer cells HeLa, liver cancer cells PLC / PRF / 5, and colon cancer cells SW480 in the logarithmic growth phase were inoculated in a six-well plate at a confluence density of about 60% and cultured overnight under conventional conditions. After the cells adhered to the wall, they were treated with DMSO, UAMC (25μM), and Lip-1 (25μM) for 24 hours, respectively. After the treatment, the cells were digested with 0.25% trypsin without EDTA for an appropriate time, and the digestion was terminated with DMEM medium containing 10% fetal bovine serum. The cells were collected by centrifugation at 800rpm / min and washed 3 times with PBS at 4℃. The cells were resuspended in 100ul of Annexin V BindingBuffer buffer, and the cells were stained with PI and annexin V in the dark, and flow cytometry was performed within 1h. The experiment was repeated 3 times.

[0042] The experimental results are as follows Figure 1 As shown, Figure 1 Schematic diagram of UAMC / Lip-1 inhibiting tumor cell proliferation, growth and promoting apoptosis. Figure 1 A is the dose-response curve of UAMC / Lip-1 in tumor cells in the experimental drug group. Figure 1 The other cancer cells in A are cervical cancer cells HeLa, breast cancer cells MDA-MB-231, and malignant melanoma cells A375. Figure 1 A shows that the cell survival rate decreases with the increase of UAMC and Lip-1 concentrations, suggesting that UAMC and Lip-1 inhibit tumor cell proliferation. Figure 1 B is a colony formation experiment diagram of cervical cancer cell HeLa, liver cancer cell PLC / PRF / 5, and colon cancer cell SW480 in different experimental drug groups. Figure 1 As shown in B, as the concentrations of UAMC and Lip-1 increased, the formation of tumor cell colonies (stained purple) decreased, suggesting that UAMC and Lip-1 inhibited tumor cell growth. Figure 1 C is a schematic diagram of apoptosis detection in cervical cancer cell HeLa, liver cancer cell PLC / PRF / 5, and colon cancer cell SW480 in different experimental drug groups. PI is propidium iodide (PI) dye, and Annexin-V is annexin-V dye. Living cells: Annexin V- / PI- (lower left quadrant); early apoptotic cells: Annexin V+ / PI- (lower right quadrant); late apoptotic cells: Annexin V+ / PI+ (upper right quadrant). Figure 1 As shown in C, UAMC and Lip-1 significantly promoted tumor cell apoptosis.

[0043] The above in vitro experimental results confirm that ferroptosis inhibitors can inhibit tumor cell proliferation and growth and promote tumor cell apoptosis.

[0044] 3. Clarify the anti-tumor effect of ferroptosis inhibitors in in vivo experiments.

[0045] 3.1 Construction of DEN-CCl4-induced mouse primary liver cancer model: 7-8 week old male C57BL / 6 mice were given an intraperitoneal injection of DEN (50 mg / kg) diluted in saline once a week for three consecutive weeks. From the fourth week, 20% CCL4 olive oil solution (0.08 mL / 10 g) was gavaged twice a week. From the sixth month, 1-2 mice were taken every two weeks and killed to observe the induction of liver cancer. After the growth of liver cancer was determined, the mice were randomly divided into 2 groups (n=6), namely: control group, given DMSO 45 mg / kg, gavage, twice a week; experimental group: given UAMC 45 mg / kg, gavage, twice a week. After 30 days, the mice were killed and the livers were taken, and the number and volume of liver tumors in each mouse were measured. Figure 2 As shown in A.

[0046] 3.2 Construction of Apc Min / + Mouse primary intestinal tumor model: Apc Min / + When the mice were about 16 weeks old, they were randomly divided into 2 groups (n=5): the control group was given DMSO 15 mg / kg, intraperitoneal injection, once every other day; the experimental group was given UAMC 15 mg / kg, intraperitoneal injection, once every other day. After 15 days, the mice were killed and the colon was removed to measure the number and volume of tumors. Figure 2 As shown in B.

[0047] like Figure 2 As shown, Figure 2 A and Figure 2 The scatter plot in B shows the average number and volume of tumors in each group (mean ± SD). It can be seen from the figure that UAMC can significantly reduce the number and volume of primary liver cancer and intestinal cancer in mice, which can confirm that ferroptosis inhibitors can play an anti-tumor effect in vivo. Combined with the results of in vitro experiments, it suggests that targeted inhibition of ferroptosis signals is a potential strategy for anti-tumor treatment.

[0048] 4. Study the synergistic effect of ferroptosis inhibitors combined with KRAS inhibitors against KRAS mutant tumors.

[0049] 4.1CCK8 cell proliferation assay:

[0050] KRAS mutant SW480 colon cancer cells were seeded in 96-well plates at a density of 7000 cells / well, and 3 replicates were set for each treatment group. The cells were cultured overnight at 37°C and 5% CO2. Key target inhibitors of KRAS mutation (concentrations as shown in the figure), including Erlotinib (targeted inhibition of EGFR), Deltarasin (targeted inhibition of KRAS), BAY-293 (targeted inhibition of KRAS), Sorafenib (targeted inhibition of RAF), Dabrafenib (targeted inhibition of BRAF), Trametinib (targeted inhibition of MEK), SCH772984 (targeted inhibition of ERK), and AZD-5363 (targeted inhibition of AKT), were combined with UAMC (10 μM) to treat SW480 cells for 48 hours, and the cell survival rate was detected by CCK8 assay.

[0051] like Figure 3 As shown, UAMC combined with KRAS inhibitors Deltarasin and BAY-293 had the best inhibitory effect on tumor cell survival.

[0052] 4.2SynergyFinder 3.0 calculates drug synergy scores:

[0053] SynergyFinder 3.0 is a standalone web application for interactive analysis and visualization of multi-drug (≥2) multi-dose combination response data. The observed drug combination response is compared with the expected response using the ZIP reference model to quantify the degree of combination effect (synergy or antagonism). The synergy score represents the average excess response caused by the drug combination. For example, a synergy score of 15 means an excess of 15% over the expected response. When the synergy score is less than -10, the drugs are antagonistic; when it is between -10 and 10, the drugs are additive; and when it is greater than 10, the drugs are synergistic. The absolute value of the synergy score is proportional to the degree of combination effect.

[0054] SW480 colon cancer cells were seeded in 96-well plates at a density of 7000 cells / well, with 3 replicates for each treatment group. The cells were cultured overnight at 37°C and 5% CO2. Tumor cells were treated with DMSO, UAMC (0, 5, 10, 15µM), BAY-293 or Deltarasin (0, 2.5, 5, 7.5µM), UAMC+BAY-293 or Deltarasin (combined at corresponding concentrations) for 24 hours, and cell survival was detected by CCK8. The CCK8 detection results were analyzed using the SynergyFinder 3.0 application to calculate the synergistic score between the two drugs. Figure 4As shown in the figure, the left column is a dose-response matrix diagram. The darker the red, the greater the inhibition rate (1-cell survival rate); the right column is a drug synergy diagram. Synergy score <-10, antagonism, green; synergy score is -10~10, superposition; synergy score >10, synergy, red. The color depth is proportional to the absolute value of the synergy score, indicating the degree of combined action. Figure 4 As shown, UAMC combined with BAY-293 or Deltarasin has a significant synergistic effect against KRAS mutant tumors.

[0055] 4.3 Colony formation assay:

[0056] SW480 cells were seeded at a density of 3000 cells / well in a 35 mm culture dish and cultured overnight under conventional conditions. After cell attachment, tumor cells were treated with DMSO, UAMC (5 μM), BAY-293 or Deltarasin (2.5 μM), UAMC+BAY-293 or Deltarasin for 7 days, and then plate colony formation assay was performed.

[0057] like Figure 5 As shown, UAMC combined with BAY-293 or Deltarasin significantly inhibited tumor cell growth.

[0058] Statistical methods

[0059] The data between the two groups were compared using the T test, with a test level of α = 0.05, and p < 0.05 was considered to be statistically significant. Statistical significance was set as follows: ns: no statistical difference; *: t test p < 0.05; **: t test p < 0.01; ***: t test p < 0.001; ****: t test p < 0.0001. The numerical values ​​of the experimental results are expressed as: mean ± standard deviation (Mean ± SD). All statistical tests were two-sided tests, and unpaired Welch' T test was performed when the variance was unequal.

[0060] In summary, the research of the present invention shows that the combination of ferroptosis inhibitors and KRAS inhibitors has a good inhibitory effect on KRAS mutated tumor cells, and the effect is significantly better than the use of ferroptosis inhibitors or KRAS inhibitors alone. The combined use of the two exerts a synergistic anti-tumor effect. Therefore, ferroptosis inhibitors and KRAS inhibitors can be used in combination or prepared as a combined preparation for the treatment of KRAS mutated tumors.

[0061] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. Use of a ferroptosis inhibitor in combination with a KRAS inhibitor for preparing a drug for treating KRAS mutated colorectal cancer, characterized in that: in, The ferroptosis inhibitor includes UAMC-3203, and the KRAS inhibitor includes one or more of Deltarasin and BAY-293.

2. The use according to claim 1, characterized in that: The molar ratio of the ferroptosis inhibitor to the KRAS inhibitor in the drug is 1:(0.17~1.5).

3. The use according to claim 2, characterized in that: The ferroptosis inhibitor in the drug is UAMC-3203, and the structural formula of UAMC-3203 is: , the KRAS inhibitor includes one of Deltarasin or BAY-293, wherein the structural formula of Deltarasin is , the structural formula of BAY-293 is The molar ratio of the UAMC-3203 to the Deltarasin is 1:(1-0.5), and the molar ratio of the UAMC-3203 to the BAY-293 is 1:(1-0.5).

4. A pharmaceutical composition for treating KRAS mutated colorectal cancer, characterized in that: The pharmaceutical composition includes a ferroptosis inhibitor and a KRAS inhibitor, wherein the ferroptosis inhibitor includes UAMC-3203, and the KRAS inhibitor includes one or more of Deltarasin and BAY-293, and the molar ratio of the ferroptosis inhibitor to the KRAS inhibitor in the drug is 1: (0.17~1.5).

5. The pharmaceutical composition according to claim 4, characterized in that The ferroptosis inhibitor in the pharmaceutical composition is UAMC-3203, and the structural formula of UAMC-3203 is: , the KRAS inhibitor includes one of Deltarasin or BAY-293, wherein the structural formula of Deltarasin is , the structural formula of BAY-293 is The molar ratio of the UAMC-3203 to the Deltarasin is 1:(1-0.5), and the molar ratio of the UAMC-3203 to the BAY-293 is 1:(1-0.5).

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