Pharmaceutical combinations and uses of FAK inhibitors and immunogenic cell death inducers

Abstract

The present invention provides use of a composition comprising a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor in the manufacture of a medicament for treating tumors. The immunogenic cell death inducer is an RNA polymerase II inhibitor, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor. The immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody. A pharmaceutical combination product of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor for treating tumors is also provided. A FAK inhibitor is provided for enhancing immunogenic cell death induced by an immunogenic cell death inducer in tumor treatment.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from Chinese Patent Application No. 202211211068.5 filed on September 30, 2022, and Chinese Patent Application No. 202311207394.3 filed on September 19, 2023, and the contents disclosed in the above Chinese patent application are incorporated herein by reference throughout this specification.

[0002] The present invention is in the field of medicinal chemistry. Specifically, the present invention relates to the treatment of tumors using focal adhesion kinase (FAK) inhibitors in combination with other drugs. [Background technology]

[0003] Tumors are the second leading disease threatening human health. Immunogenic cell death (ICD) is an additive effect of programmed cell death. Upon contact with chemotherapy or targeted therapeutic drugs, cancer cells can activate internal stress signals, including endoplasmic reticulum (ER) stress and oxidative stress. Under the influence of stress signals, cells first attempt to repair the damage. If the damage exceeds their repair capacity, the cells initiate the programmed death process. This process is often accompanied by the release of damage-associated molecular patterns (DAMPs). These DAMPs are specifically recognized by pattern recognition receptors on antigen-presenting cells (APCs) in the organism, inducing APC maturation, differentiation, and activation, and then presenting them to immune cells, such as effector T cells, in a stepwise manner. This allows immune cells to form antigenic memory and specifically recognize and kill tumor cells of the same origin when they encounter them again. The new specific immune response against tumors initiated by ICDs can enhance the effects of immune checkpoint inhibitors (ICIs) by increasing their sensitivity, resulting in antitumor responses with durable immunological memory.

[0004] FAK, also known as protein tyrosine kinase 2 (PTK2), is a non-receptor tyrosine kinase and a key component of focal adhesion complexes. FAK plays an important role in mediating integrin and growth factor signals to regulate tumor cell invasion, proliferation, and survival.

[0005] Currently, there is a need to improve the efficacy of immunogenic cell death inducers in clinical practice, and therefore, it is necessary to find ways to improve the therapeutic efficacy of single-agent immunogenic cell death inducers and further overcome the problem of drug resistance. Summary of the Invention

[0006] According to one embodiment of the present disclosure, there is provided a use of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0007] According to another embodiment of the present disclosure, there is provided a pharmaceutical combination product of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor for treating a tumor in a subject, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0008] According to another embodiment of the present disclosure, there is provided a method for treating a tumor, comprising administering therapeutically effective amounts of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor to a subject in need thereof, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0009] Another embodiment of the present disclosure provides a kit or pharmaceutically acceptable composition comprising: (a) a FAK inhibitor; (b) an immunogenic cell death inducer; and (c) an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0010] According to another aspect of the present disclosure, there is provided a use of a FAK inhibitor and an immunogenic cell death inducer in the manufacture of a drug for treating a tumor, wherein the FAK inhibitor enhances immunogenic cell death induced by the immunogenic cell death inducer, and the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0011] According to another aspect of the present disclosure, there is provided a FAK inhibitor for enhancing immunogenic cell death induced by an immunogenic cell death inducer in the treatment of a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0012] According to another aspect of the present disclosure, there is provided a method for treating a tumor, comprising administering therapeutically effective amounts of a FAK inhibitor and an immunogenic cell death inducer to a subject in need thereof, wherein the FAK inhibitor enhances immunogenic cell death induced by the immunogenic cell death inducer, and the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0013] According to another embodiment of the present disclosure, there is provided a use of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor in combination for the manufacture of a medicament for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0014] According to another embodiment of the present disclosure, there is provided a use of a FAK inhibitor together with an immunogenic cell death inducer and an immune checkpoint inhibitor in the manufacture of a combination drug for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0015] According to another embodiment of the present disclosure, there is provided a use of an immunogenic cell death inducer, together with a FAK inhibitor and an immune checkpoint inhibitor, in the manufacture of a combination drug for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0016] According to another embodiment of the present disclosure, there is provided a use of an immune checkpoint inhibitor together with a FAK inhibitor and an immunogenic cell death inducer in the manufacture of a combination drug for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0017] According to another embodiment of the present disclosure, there is provided a use of a FAK inhibitor in combination with an immunogenic cell death inducer and an immune checkpoint inhibitor in the manufacture of a medicament for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0018] According to another embodiment of the present disclosure, there is provided a use of an immunogenic cell death inducer in the manufacture of a medicament for treating a tumor in combination with a FAK inhibitor and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0019] According to another embodiment of the present disclosure, there is provided a use of an immune checkpoint inhibitor in combination with a FAK inhibitor and an immunogenic cell death inducer in the manufacture of a medicament for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0020] Another embodiment of the present disclosure provides a kit comprising a FAK inhibitor and instructions indicating that the FAK inhibitor can be used to treat tumors in combination with an immunogenic cell death inducer and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0021] Another embodiment of the present disclosure provides a kit comprising an immunogenic cell death inducer and instructions indicating that the immunogenic cell death inducer can be used to treat tumors in combination with a FAK inhibitor and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0022] Another embodiment of the present disclosure provides a kit comprising an immune checkpoint inhibitor and instructions indicating that the immune checkpoint inhibitor can be used to treat tumors in combination with a FAK inhibitor and an immunogenic cell death inducer, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0023] According to another aspect of the present disclosure, there is provided a method for treating a tumor, comprising administering therapeutically effective amounts of a FAK inhibitor and an immunogenic cell death inducer to a subject in need thereof, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0024] According to another aspect of the present disclosure, there is provided a pharmaceutical combination product of a FAK inhibitor and an immunogenic cell death inducer for treating tumors in a subject in need thereof, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0025] According to another aspect of the present disclosure, there is provided a use of a FAK inhibitor and an immunogenic cell death inducer in the manufacture of a combination drug for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0026] According to another aspect of the present disclosure, there is provided a use of a FAK inhibitor together with an immunogenic cell death inducer in the manufacture of a combination drug for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0027] According to another aspect of the present disclosure, there is provided a use of an immunogenic cell death inducer in the manufacture of a combination drug for treating a tumor together with a FAK inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0028] According to another aspect of the present disclosure, there is provided a use of a FAK inhibitor and an immunogenic cell death inducer in combination in the manufacture of a medicament for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0029] According to another aspect of the present disclosure, there is provided a use of a FAK inhibitor in combination with an immunogenic cell death inducer in the manufacture of a medicament for treating a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0030] According to another aspect of the present disclosure, there is provided a use of an immunogenic cell death inducer in the manufacture of a medicament for treating a tumor in combination with a FAK inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0031] Another aspect of the present disclosure provides a kit comprising a FAK inhibitor and instructions indicating that the FAK inhibitor can be used to treat tumors in combination with an immunogenic cell death inducer, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0032] Another aspect of the present disclosure provides a kit comprising an immunogenic cell death inducer and instructions indicating that the immunogenic cell death inducer can be used to treat tumors in combination with a FAK inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0033] Optionally, the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof, more preferably IN10018, or a pharmaceutically acceptable salt thereof, particularly IN10018 tartrate, wherein the structure of IN10018 is as follows: [ka]

[0034] The defactinib is also known as defactinib, and has a CAS number of 1345713-71-4, the GSK2256098 has a CAS number of 1224887-10-8, the PF-00562271 has a CAS number of 717907-75-0, the VS-4718 has a CAS number of 1061353-68-1, the APG-2449 is developed by Yasheng Pharmaceutical, and the AMP945 has a CAS number of 1393653-34-3.

[0035] Optionally, the immunogenic cell death inducer is an inhibitor of RNA polymerase II.

[0036] Optionally, the inhibitor of RNA polymerase II is lurbinectedin, SEL-120, or a pharmaceutically acceptable salt thereof.

[0037] Lurbinectedin has a CAS number of 497871-47-3, and SEL-120 has a CAS number of 1609522-33-9.

[0038] Optionally, the inhibitor of RNA polymerase II is lurbinectedin.

[0039] Optionally, the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

[0040] Optionally, the ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib, or a pharmaceutically acceptable salt thereof, in particular crizotinib, entrectinib, or a pharmaceutically acceptable salt thereof.

[0041] Crizotinib has a CAS number of 877399-52-5, SIM-0201 was developed by Sunsheng Pharmaceutical, XZP-3621 was developed by Xuanzhu Biological, TQ-B3139 was developed by Zhengda Tianqing, folitinib (SAF-189s) was jointly developed by Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chongqing Fuchuang Pharmaceutical Research Co., Ltd., ceritinib has a CAS number of 1032900-25-6, and lorlatinib (PF-06463922, lorlatinib) has a CAS number of 1454846-35-5. Alectinib has a CAS number of 1256580-46-7, Ensartinib has a CAS number of 1365267-27-1, APG-2449 was developed by Yashiro Pharmaceutical, Brigatinib has a CAS number of 1197953-54-0, TQ-B3101 was developed by Shodai Tenka, Entrectinib has a CAS number of 1108743-60-7, and Repotrectinib has a CAS number of 1802220-02-5.

[0042] Optionally, the ALK / ROS1 inhibitor is crizotinib or a pharmaceutically acceptable salt thereof.

[0043] Optionally, the immunogenic cell death inducer is a KRAS G12C inhibitor.

[0044] Optionally, the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, Sotorasib (sotorasib / AMG510), Adagrasib (MRTX849), GDC-6036, or a pharmaceutically acceptable salt thereof, in particular D-1553, Sotorasib (sotorasib / AMG510), or a pharmaceutically acceptable salt thereof.

[0045] D-1553 was developed by Yifang Biologicals, ARS-3248 was developed by Araxes, GF-105 was developed by GenFlee Therapeutics, JAB-21822 was developed by Jakobsen, JDQ-443 was developed by Nuohua, LY-3537982 has a CAS number of 2414198-64-2, sotorasib (AMG510) has a CAS number of 2296729-00-3, adagrasib (MRTX849) has a CAS number of 2326521-71-3, and GDC-6036 has a CAS number of 2417987-45-0.

[0046] Optionally, the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

[0047] Optionally, the immunogenic cell death inducer is a KRAS G12D inhibitor.

[0048] Optionally, the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000, or a pharmaceutically acceptable salt thereof.

[0049] The CAS number of MRTX1133 is 2621928-55-8, JAB-22000 is developed by Jakobsen Pharmaceuticals, and HRS-4642 is developed by Hengrui Pharmaceuticals.

[0050] Optionally, the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

[0051] Optionally, the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

[0052] Optionally, the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and further, the anti-PD-1 / PD-L1 antibody is selected from the group consisting of pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, umab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, envafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181.

[0053] Optionally, the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and further, the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001.

[0054] Optionally, the immune checkpoint inhibitor is a TIGIT antibody, and further, the TIGIT antibody is Ociperlimab (BGB-A1217), Vibostolimab, domvanalimab (AB154), Tiragolumab, Belrestotug, Etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321.

[0055] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is lurbinectedin, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor.

[0056] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is lurbinectedin, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

[0057] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor.

[0058] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

[0059] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor.

[0060] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

[0061] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor.

[0062] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is a TIGIT antibody.

[0063] Optionally, the FAK inhibitor, the immunogenic cell death inducer and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

[0064] Optionally, the tumor is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, adipose tissue cancer, and the like. tumors, nasopharyngeal carcinoma, neuroendocrine tumors, ovarian cancer, salivary gland cancer, metastatic tumors from spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematopoietic malignancies such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0065] Optionally, the tumor is preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), gastric cancer, malignant melanoma, or pancreatic cancer.

[0066] Optionally, the tumor is lung cancer, colon cancer (including colorectal cancer), or breast cancer.

[0067] In order to more clearly describe the technical means in the embodiments of the present disclosure, the drawings of the embodiments will be briefly described below. Obviously, the drawings in the following description are only related to some embodiments of the present disclosure and are not intended to limit the present invention. [Brief explanation of the drawings]

[0068] [Figure 1] 1 shows curves showing the inhibitory effect of lurbinectedin and its combination with IN10018 on the proliferation of mouse colon cancer CT26 cells versus drug concentration. [Figure 2] White light micrographs of mouse colon carcinoma CT26 cells taken after 48 hours of incubation with the drug are shown. [Figure 3] The percentage of CRT-positive cells after incubating mouse colon cancer CT26 cells with drugs for 48 hours (Figure 3a) is shown, and the percentage of Annexin V-positive cells after incubating mouse colon cancer CT26 cells with drugs for 48 hours (Figure 3b) is shown. [Figure 4] 1 shows curves showing the inhibitory effect of MRTX1133 and its combination with IN10018 on the proliferation of mouse colon cancer CT26 cells versus drug concentration. [Figure 5] White light micrographs of mouse colon carcinoma CT26 cells taken after 48 hours of incubation with the drug are shown. [Figure 6] The percentage of CRT-positive cells after incubating mouse colon cancer CT26 cells with drugs for 48 hours (Figure 6a) is shown, and the percentage of Annexin V-positive cells after incubating mouse colon cancer CT26 cells with drugs for 48 hours (Figure 6b) is shown. [Figure 7] 1 shows curves showing the inhibitory effect of MRTX1133 and its combination with IN10018 on the proliferation of mouse lung cancer KPL cells versus drug concentration. [Figure 8]White light micrographs of mouse lung carcinoma KPL cells taken after 48 hours of incubation with the drug are shown. [Figure 9] The percentage of CRT-positive cells after incubating mouse lung cancer KPL cells with the drug for 48 hours (FIG. 9a) is shown, and the percentage of Annexin V-positive cells after incubating mouse lung cancer KPL cells with the drug for 48 hours (FIG. 9b) is shown. [Figure 10] The percentage of calreticulin (CRT)-positive cells after incubating mouse colon cancer CT26 cells with drugs for 48 hours (Figure 10a) is shown, and the percentage of Annexin-V-positive cells after incubating mouse colon cancer CT26 cells with drugs for 48 hours (Figure 10b) is shown. [Figure 11] 1 shows the weight change of tumor-bearing mice administered with the test article in a mouse colon cancer CT26-KRAS G12C allograft tumor model. Data points represent group mean weight, and error bars represent standard error of the mean (SEM). [Figure 12] Figure 1 shows the relative weight change (%) of tumor-bearing mice treated with the test article in a mouse colon cancer CT26-KRAS G12C allograft tumor model. Relative weight change is calculated based on the animal's weight at the start of treatment. Data points represent the group mean weight change percentage, and error bars represent the standard error of the mean (SEM). [Figure 13] 1 shows tumor growth curves of tumor-bearing mice administered test drugs in a mouse colon cancer CT26-KRAS G12C allograft tumor model. Data points represent group mean tumor volumes, and error bars represent standard error of the mean (SEM). [Figure 14] 1 shows tumor growth curves after drug administration in a BALB / c mouse subcutaneous allograft tumor model of mouse colon cancer CT26 cells. Data points represent group mean tumor volumes, and error bars represent standard error of the mean (SEM). [Figure 15] 1 shows tumor growth curves after drug administration in a BABL / c mouse subcutaneous allograft tumor model of mouse colon cancer CT26 cells. Data points represent group mean tumor volumes, and error bars represent standard error of the mean (SEM). [Figure 16]This shows the weight change curve after drug administration in a BALB / c mouse subcutaneous allograft tumor model of mouse colon cancer CT26 cells. Data points represent the group mean weight, and error bars represent the standard error of the mean (SEM). [Figure 17] The percentage of calreticulin (CRT)-positive cells after incubating mouse breast cancer 4T1 cells with drugs for 48 hours (Figure 17a) is shown, and the percentage of Annexin-V-positive cells after incubating mouse breast cancer 4T1 cells with drugs for 48 hours (Figure 17b) is shown. [Figure 18] The percentage of calreticulin (CRT)-positive cells after incubating mouse breast cancer 4T1 cells with drugs for 48 hours (Figure 18a) is shown, and the percentage of Annexin-V-positive cells after incubating mouse breast cancer 4T1 cells with drugs for 48 hours (Figure 18b) is shown. DETAILED DESCRIPTION OF THE INVENTION

[0069] In order to clarify the objectives, technical means and advantages of the embodiments of the present disclosure, the technical means in the embodiments of the present disclosure will be clearly and completely described below with reference to the drawings in the embodiments of the present disclosure. Obviously, the described embodiments are only some embodiments of the present disclosure, but not all embodiments. Based on the described embodiments of the present disclosure, any other embodiments that can be obtained by a person skilled in the art without any creative effort fall within the scope of protection of the present invention.

[0070] The present invention may be embodied in other specific forms without departing from the essential attributes of the present invention. It should be understood that, unless inconsistent, any and all embodiments of the present invention may be combined with technical features of any one or more other embodiments to obtain another embodiment. The present invention includes the other embodiment obtained from such a combination.

[0071] All publications and patents mentioned in this disclosure are incorporated herein by reference in their entirety. If the terminology or usage used in any publication or patent incorporated by reference conflicts with the terminology or usage used in this disclosure, the terminology and usage in this disclosure shall control.

[0072] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter discussed above.

[0073] Unless otherwise defined, all technical and scientific terms used herein have their common meaning within the field to which the subject matter sought to be protected belongs. In the event that a term has multiple definitions, those in this specification are to be used.

[0074] All numerical values ​​of quantitative nature, such as dosages, set forth in the specification and claims, except in the examples or where otherwise expressly stated, should be understood to be modified in all instances by the term "about." Furthermore, any numerical range recited herein is intended to include all subranges within that range and any combination of each endpoint of that range or subrange.

[0075] As used in this disclosure, words such as "comprise," "contain," or "comprises" and similar words are intended to mean that the elements appearing before the word cover the elements listed after the word and their equivalents, and do not exclude unlisted elements. As used herein, the terms "comprise" or "comprise" may be open, semi-closed, and closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0076] definition As used herein, the following terms and symbols have the following meanings, unless the context dictates otherwise. As used herein, the term "FAK inhibitor" refers to an effective inhibitor of FAK, suitable for mammals, particularly humans. In some embodiments, the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof, and the structure of IN10018 is as follows: [ka]

[0077] Defactinib, also known as defactinib, has a CAS number of 1345713-71-4, and GSK2256098 has a CAS number of 1224887-10-8. PF-00562271 has a CAS number of 717907-75-0, VS-4718 has a CAS number of 1061353-68-1, APG-2449 is developed by Yasheng Pharmaceutical, and AMP945 has a CAS number of 1393653-34-3. In some embodiments, the FAK inhibitor is preferably IN10018, defactinib, AMP945, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, particularly IN10018 tartrate.

[0078] As used herein, the term "immunogenic cell death inducer" refers to a substance that induces immunogenic cell death (ICD) in an anti-tumor immune response. Immunogenic cell death (ICD) is a specific type of regulated cell death (RCD) that is induced by stress and can induce adaptive immunity against antigens of dead cells. The immunogenic cell death inducers described herein are RNA polymerase II inhibitors, ALK / ROS1 inhibitors, KRAS G12C inhibitors, or KRAS G12D inhibitors.

[0079] In some embodiments, the immunogenic cell death inducer may be an inhibitor of RNA polymerase II. In some embodiments, the RNA polymerase II inhibitor is lurbinectedin, SEL-120, or a pharmaceutically acceptable salt thereof. Lurbinectedin has CAS number 497871-47-3, and SEL-120 has CAS number 1609522-33-9. In some embodiments, the RNA polymerase II inhibitor is lurbinectedin.

[0080] In some embodiments, the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

[0081] In some embodiments, the ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib, or a pharmaceutically acceptable salt thereof, in particular crizotinib, entrectinib, or a pharmaceutically acceptable salt thereof.

[0082] The CAS number of crizotinib is 877399-52-5, SIM-0201 is developed by Sunsheng Pharmaceutical, XZP-3621 is developed by Xuanzhu Biological, TQ-B3139 is developed by Zhengda Tianqing, folitinib (SAF-189s) is jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chongqing Fuchuang Pharmaceutical Research Co., Ltd., ceritinib has a CAS number of 1032900-25-6, and lorlatinib (PF-06463922, lorlatinib) has a CAS number of 1454846-35-5. Alectinib has a CAS number of 1256580-46-7, Ensartinib has a CAS number of 1365267-27-1, APG-2449 was developed by Yashiro Pharmaceutical, Brigatinib has a CAS number of 1197953-54-0, TQ-B3101 was developed by Shodai Tenka, Entrectinib has a CAS number of 1108743-60-7, and Repotrectinib has a CAS number of 1802220-02-5.

[0083] In some embodiments, the ALK / ROS1 inhibitor is crizotinib or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the immunogenic cell death inducer is a KRAS G12C inhibitor.

[0085] In some embodiments, the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, sotorasib (AMG510), adagrasib (MRTX849), GDC-6036, or a pharmaceutically acceptable salt thereof, particularly D-1553, sotorasib (AMG510), or a pharmaceutically acceptable salt thereof.

[0086] The above D-1553 was developed by Yifang Biologicals, ARS-3248 was developed by Araxes, GF-105 was developed by GenFleet Therapeutics, JAB-21822 was developed by Jakobsen, JDQ-443 was developed by Nuohua, LY-3537982 has a CAS number of 2414198-64-2, sotorasib (AMG510) has a CAS number of 2296729-00-3, adagrasib (MRTX849) has a CAS number of 2326521-71-3, and GDC-6036 has a CAS number of 2417987-45-0.

[0087] In some embodiments, the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the immunogenic cell death inducer is a KRAS G12D inhibitor.

[0089] In some embodiments, the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000, or a pharmaceutically acceptable salt thereof.

[0090] The CAS number of the above MRTX1133 is 2621928-55-8, JAB-22000 was developed by Jakobsen Pharmaceuticals, and HRS-4642 was developed by Hengrui Pharmaceuticals.

[0091] In some embodiments, the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

[0092] As used herein, the term "immune checkpoint inhibitor" refers to a drug that can enhance immune system activity by modulating immune checkpoint pathways (e.g., PD-1, PDL-1, TIGIT, CTLA-4, LAG-3, TIM-3, etc.). In some embodiments, the immune checkpoint inhibitor is a PD-1 / PD-L1 (programmed cell death protein 1) pathway antagonist (also referred to as a "PD-1 inhibitor") or a TIGIT inhibitor. PD-1 inhibitors are also referred to as PD-1 / PD-L1 inhibitors in the present disclosure. For example, in the treatment methods, drugs, and uses disclosed herein, the PD-1 / PD-L1 inhibitor is a PD-1 / PD-L1 antibody, such as pembrolizumab (Keytruda), tislelizumab (Beigene), nivolumab, toripalimab (Tokuei), atezolizumab (Tecentriq), Examples of PD-1 inhibitors include, but are not limited to, durvalumab (Imfinzi / durvalumab / durvalumab), avelumab (Avelumab / Bavencio), atezolizumab (MPDL3280A / Atezolizumab / Tecentriq / T drug), BMS-936559 (a fully human anti-PD-L1 IgG4 monoclonal antibody), GS-4224, AN-4005, or MX-10181. In some preferred embodiments, the PD-1 inhibitor is toripalimab. In some embodiments, the PD-1 inhibitor treats a human subject. In some embodiments, the PD-1 is human PD-1. PD-1 / PD-L1 inhibitors also include PD-1 / PD-L1 small molecule inhibitors, such as INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001.

[0093] TIGIT (also known as WUCAM, Vstm3, and VSIG9) is a receptor of the Ig superfamily and a novel immune checkpoint following PD-1 / PD-L1. For example, in the therapeutic methods, drugs, and uses of the present disclosure, the immune checkpoint inhibitor is a TIGIT inhibitor, including, but not limited to, osipelimab (Ociperlimab / BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, belrestotug, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. In some embodiments, the TIGIT inhibitor treats a human subject. For the avoidance of doubt, all references to antibodies herein include diabodies.

[0094] As used herein, a "pharmaceutical combination" or "pharmaceutical combination product" may refer to a fixed combination in a single dosage unit form (e.g., all active drug ingredients are present in a single dosage form) or a kit of combined administration products, or may refer to a combination of one drug and instructions for use of that drug in combination with one or more other drugs.

[0095] As used herein, "combination therapy" or "combined drug" refers to the use of one drug in combination with one or more other drugs to treat a disease, and includes not only the combination of one drug with one or more other drugs, but also the combination of one drug with instructions indicating that the drug can be used in combination with one or more other drugs.

[0096] As used herein, the term "administered simultaneously or sequentially" refers to the administration of two or more drugs simultaneously or at a fixed time interval in one administration cycle (e.g., within 4 weeks, 3 weeks, 2 weeks, 1 week, or 24 hours), where the drug administration modes (e.g., oral, intravenous, intramuscular, or subcutaneous administration) may be the same or different, and the administration frequency / cycle of the two or more drugs may be the same or different. When the therapeutic method, product, or use of the present disclosure involves two drugs, the two drugs may be administered simultaneously or separately at a fixed time interval. When the therapeutic method, product, or use of the present disclosure involves three drugs, the three drugs may be administered at the same time, two drugs may be administered at a specific time and the remaining drug may be administered at a different time, or all three drugs may be administered at different times.

[0097] In some embodiments, the PD-1 / PD-L1 inhibitor is administered intravenously (e.g., as an intravenous infusion), subcutaneously, or orally. Preferably, the PD-1 / PD-L1 inhibitor is administered intravenously.

[0098] In some embodiments, the TIGIT inhibitor is administered intravenously (e.g., as an intravenous infusion), subcutaneously, or orally. Preferably, the TIGIT inhibitor is administered intravenously.

[0099] The ability of immune checkpoint inhibitors to treat cancer depends on the presence of tumor antigen-specific T cells within tumor tissue. This requires that tumor tissue express antigens that distinguish it from its non-transformed counterparts, for example, by novel protein products called neoantigens. Tumor neoantigen burden strongly correlates with immunogenicity and sensitivity (e.g., to checkpoint inhibitor therapy), meaning that poorly immunogenic tumors should be highly resistant to these drugs. Therapies that release tumor antigens that can be taken up by APCs, such as those that induce immunogenic cell death (ICD), may effectively promote anti-tumor immunity, particularly when combined with checkpoint inhibitors.

[0100] As used herein, the term "treatment" refers to the administration of one or more drug substances to a subject having a disease or symptoms of said disease to cure, alleviate, relieve, alter, treat, improve, ameliorate or affect said disease or symptoms of said disease. In some embodiments, said disease is a tumor or cancer.

[0101] The term "tumor" as used herein refers to an abnormal lesion formed by the abnormal clonal proliferation of certain cells in local tissues that have lost normal growth regulation at the genetic level under the influence of various carcinogenic factors. Examples of such tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, and neuroendocrine carcinoma. The tumors include, but are not limited to, secretory tumors, ovarian cancer, salivary gland cancer, metastatic tumors from spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematopoietic malignancies such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). In some embodiments, the tumor is preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), gastric cancer, malignant melanoma, or pancreatic cancer. In some embodiments, the tumor is lung cancer, colon cancer (including colorectal cancer), or breast cancer.

[0102] As used herein, the term "subject" or "test subject" refers to mammals and non-mammals. Mammals refer to any member of the mammalian genus, including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cows, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds. The term "subject" is not limited to a particular age or sex. In some embodiments, the subject is a human.

[0103] As used herein, the term "pharmaceutically acceptable" refers to non-toxic, biologically tolerable, and suitable for administration to a subject.

[0104] As used herein, the term "pharmaceutically acceptable salt" refers to an acid addition salt that is non-toxic, biologically acceptable, and suitable for administration to a subject, and includes, but is not limited to, acid addition salts formed with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like, and acid addition salts formed with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts formed with alkanedicarboxylic acids of the formula HOOC-(CH)-COOH, where n is 0-4.

[0105] Pharmaceutically acceptable acid addition salts may also be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine, without undue experimentation, various synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable acid addition salts.

[0106] As used herein, the term "pharmaceutically acceptable composition" refers to a composition that must be chemically and / or toxicologically compatible with other components of the formulation and / or the subject being treated therewith. As used herein, the term "therapeutically effective amount" generally refers to an amount sufficient to provide a beneficial therapeutic effect to the subject. The therapeutically effective amount of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, medical history of the subject, health status of the subject, responsiveness of the subject to the drug, etc.).

[0107] As used herein, the term "inhibition" refers to a decrease in the baseline activity of a biological activity or process.

[0108] As used herein, the term "kit" refers to a box for containing chemical reagents for detecting chemical components, residual drugs, types of viruses, etc. A kit according to the present invention may include (i) one, two, or three of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor, and (ii) instructions indicating that the FAK inhibitor, the immunogenic cell death inducer, and the immune checkpoint inhibitor can be used to treat a tumor in a subject, where the immunogenic cell death inducer is an RNA polymerase II inhibitor, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor. In one embodiment, the kit includes (i) a FAK inhibitor and (ii) instructions indicating that the FAK inhibitor, the immunogenic cell death inducer, and the immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit includes (i) an immunogenic cell death inducer and (ii) instructions indicating that the FAK inhibitor, the immunogenic cell death inducer, and the immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) an immune checkpoint inhibitor and (ii) instructions indicating that the FAK inhibitor, the immunogenic cell death inducer, and the immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) a FAK inhibitor, the immunogenic cell death inducer, and the immune checkpoint inhibitor and (ii) instructions indicating that the FAK inhibitor, the immunogenic cell death inducer, and the immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) a FAK inhibitor and (ii) instructions indicating that the FAK inhibitor and the immunogenic cell death inducer can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) an immunogenic cell death inducer and (ii) instructions indicating that the immunogenic cell death inducer and the FAK inhibitor can be used to treat a tumor in a subject.

[0109] The components of the kit may be contained in separate containers. Optionally, two or more components may be contained in the same container. For example, the kit may include a first container, a second container, a third container, and a package insert, where the first container contains at least one dose of a drug including a FAK inhibitor, the second container contains at least one dose of an immunogenic cell death inducer, and the third container contains at least one dose of an immune checkpoint inhibitor drug, and the package insert includes instructions for using the drug to treat a tumor in a subject. The first container, the second container, and the third container may be the same or different shapes (e.g., vials, syringes, and bottles) and / or materials (e.g., plastic or glass). The kit may further include other materials useful for administering the drug, such as diluents, filters, IV bags and pipelines, needles, and syringes.

[0110] The exact amount of FAK inhibitor, immunogenic cell death inducer, or immune checkpoint inhibitor administered to a subject depends on various factors, such as the specific drug or compound, drug formulation, route of administration, type of disease, symptoms, and identity of the subject or host being treated, but can still be routinely determined by one of ordinary skill in the art. For example, determining an effective amount also depends on the degree, severity, and type of cell proliferation. Those of ordinary skill in the art can determine the appropriate dose depending on these and other factors.

[0111] The FAK inhibitor, immunogenic cell death inducer or immune checkpoint inhibitor may be administered by an appropriate route, such as oral, intravenous, intramuscular or subcutaneous administration.

[0112] For example, when administered orally, a drug may be administered orally with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. These may be enclosed in hard or soft-shell gelatin capsules, compressed into tablets, or directly incorporated into the patient's food. For example, a drug may be combined with one or more excipients and used in the form of an ingestible tablet, buccal tablet, troche, capsule, elixir, suspension, syrup, wafer, or the like. Tablets, troches, pills, capsules, and the like may further contain adhesives such as tragacanth gum, gum arabic, cornstarch, or gelatin; excipients such as dibasic calcium phosphate; disintegrating agents such as cornstarch, potato starch, or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, fructose, lactose, or aspartame; or flavoring agents.

[0113] For example, for intravenous or intraperitoneal administration as an infusion or injection, solutions of the drug can be prepared in water, optionally mixed with a nontoxic surfactant.

[0114] Exemplary pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injectable or infusion solutions or dispersions. In all cases, the ultimate dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage.

[0115] Sterile injectable solutions can be prepared by incorporating the required amount of the drug in an appropriate solvent with various other ingredients as described above, followed by filtration sterilization. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze-drying techniques, which can produce powders of the active ingredient plus any other desired ingredients present after prior sterilization filtration.

[0116] The amount of FAK inhibitor, immunogenic cell death inducer, or immune checkpoint inhibitor required for treatment will vary depending on the particular reagent selected, the route of administration, the nature of the disease being treated, and the age and condition of the patient, and is ultimately determined by the attending physician or clinician. However, generally, the dose will be in the range of about 0.1 to about 50 mg / kg body weight daily.

[0117] The FAK inhibitor is administered in a dosage range of 5 mg to 500 mg per day in adults. In a specific embodiment, IN10018 or a pharmaceutically acceptable salt thereof is administered in a dosage range of 5 mg to 100 mg per day in adults, for example, IN10018 or a pharmaceutically acceptable salt thereof is administered in a dosage range of 25 mg to 100 mg per day in adults, the dosages being calculated on a free base basis.

[0118] The dose range of the immunogenic cell death inducers administered to adults is determined depending on the drug. In some embodiments, the RNA polymerase II inhibitor is administered at a dose of 1 to 25 mg / m for 21 days (treatment cycle) in adults. 2 In some specific embodiments, lurbinectedin is administered in a dose range of 1 to 5 mg / m for 21 days in adults. 2In some embodiments, the ALK / ROS1 inhibitor is administered in a dose range of 2 to 1000 mg daily in adults. In some specific embodiments, crizotinib is administered in a dose range of 50 to 500 mg daily in adults. In some specific embodiments, the KRAS G12C inhibitor is administered in a dose range of 10 to 500 mg daily in adults. In some specific embodiments, D-1553 is administered in a dose range of 10 to 250 mg daily in adults. In some embodiments, the KRAS G12D inhibitor is administered in a dose range of 25 to 800 mg daily in adults. In some specific embodiments, MRTX1133 is administered in a dose range of 25 to 600 mg daily in adults. All of the above dosages are calculated on the free base.

[0119] The immune checkpoint inhibitor is administered at a dose of 2 to 10 mg / kg or 50 to 1200 mg for adults once every two to three weeks. In a specific embodiment, the immune checkpoint inhibitor is administered at a dose of 3 to 10 mg / kg or 100 to 1200 mg for adults once every two to three weeks.

[0120] Technical and scientific terms used herein that are not specifically defined have the meaning commonly understood by one of ordinary skill in the art of the present invention.

[0121] In some embodiments, the present disclosure further discloses the following embodiments:

[0122] 1. A FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor for use in a method for treating a tumor in a subject, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0123] 2. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 1, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945 or a pharmaceutically acceptable salt thereof, more preferably IN10018 or a pharmaceutically acceptable salt thereof, in particular IN10018 tartrate, wherein the structure of IN10018 is as follows: [ka]

[0124] 3. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 1 or 2, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II.

[0125] 4. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to any one of embodiments 1 to 3, wherein the inhibitor of RNA polymerase II is lurbinectedin, SEL-120 or a pharmaceutically acceptable salt thereof.

[0126] 5. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 3 or 4, wherein the inhibitor of RNA polymerase II is lurbinectedin.

[0127] 6. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 1 or 2, wherein the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

[0128] 7. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 6, wherein the ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib or a pharmaceutically acceptable salt thereof, in particular crizotinib, entrectinib or a pharmaceutically acceptable salt thereof.

[0129] 8. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 6 or 7, wherein the ALK / ROS1 inhibitor is crizotinib or a pharmaceutically acceptable salt thereof.

[0130] 9. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 1 or 2, wherein the immunogenic cell death inducer is a KRAS G12C inhibitor.

[0131] 10. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 9, wherein the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, Sotorasib (sotorasib / AMG510), Adagrasib (MRTX849), GDC-6036 or a pharmaceutically acceptable salt thereof, in particular D-1553, Sotorasib (sotorasib / AMG510) or a pharmaceutically acceptable salt thereof.

[0132] 11. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 9 or 10, wherein the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

[0133] 12. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 1 or 2, wherein the immunogenic cell death inducer is a KRAS G12D inhibitor.

[0134] 13. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 12, wherein the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000 or a pharmaceutically acceptable salt thereof.

[0135] 14. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 12 or 13, wherein the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

[0136] 15. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to any one of embodiments 1 to 14, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

[0137] 16. The immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and the anti-PD-1 / PD-L1 antibody is selected from the group consisting of pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, and atezolizumab. 16. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to any one of embodiments 1 to 15, wherein the FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor is atezolizumab, camrelizumab, sintilimab, cemiplimab, envafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.

[0138] 17. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to any one of embodiments 1 to 15, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and further wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001.

[0139] 18. The immune checkpoint inhibitor is a TIGIT antibody, and further, the TIGIT antibody is selected from the group consisting of osiperlimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, belrestotug, etigilimab, ONO-4686, JS-006, and AZ 16. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor of any one of embodiments 1 to 15, wherein the FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor is D-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.

[0140] 19. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to embodiment 1, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is lurbinectedin, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0141] 20. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to embodiment 1, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0142] 21. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to embodiment 1, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0143] 22. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor described in embodiment 1, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is a TIGIT antibody.

[0144] 23. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to any one of embodiments 1 to 22, wherein the FAK inhibitor, the immunogenic cell death inducer and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

[0145] 24. The tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine tumor, ovarian cancer, salivary gland cancer, metastatic tumors from spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-small cell carcinoma, ovarian cancer, salivary gland cancer, ovarian ... The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to any one of embodiments 1 to 23, which are Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematopoietic malignancies, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, or pancreatic cancer.

[0146] 25. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 24, wherein the tumor is lung cancer, colon cancer (including colorectal cancer) or breast cancer.

[0147] 26, (a) FAK inhibitor and (b) an immunogenic cell death inducer; (c) an immune checkpoint inhibitor, The kit or pharmaceutically acceptable composition, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0148] 27. The kit or composition according to embodiment 26, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945 or a pharmaceutically acceptable salt thereof, more preferably IN10018 or a pharmaceutically acceptable salt thereof, particularly IN10018 tartrate, and the structure of IN10018 is as follows: [ka]

[0149] 28. The kit or composition of embodiment 26 or 27, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II.

[0150] 29. The kit or composition of embodiment 28, wherein the inhibitor of RNA polymerase II is lurbinectedin, SEL-120, or a pharmaceutically acceptable salt thereof.

[0151] 30. The kit or composition of embodiment 28 or 29, wherein the inhibitor of RNA polymerase II is lurbinectedin.

[0152] 31. The kit or composition of embodiment 26 or 27, wherein the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

[0153] 32. The kit or composition according to embodiment 31, wherein the ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib, or a pharmaceutically acceptable salt thereof, in particular, crizotinib, entrectinib, or a pharmaceutically acceptable salt thereof.

[0154] 33. The kit or composition according to embodiment 31 or 32, wherein the ALK / ROS1 inhibitor is crizotinib or a pharmaceutically acceptable salt thereof.

[0155] 34. The kit or composition of embodiment 26 or 27, wherein the immunogenic cell death inducer is a KRAS G12C inhibitor.

[0156] 35. The kit or composition of embodiment 34, wherein the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, Sotorasib (sotorasib / AMG510), Adagrasib (MRTX849), GDC-6036, or a pharmaceutically acceptable salt thereof, in particular D-1553, Sotorasib (sotorasib / AMG510), or a pharmaceutically acceptable salt thereof.

[0157] 36. The kit or composition of embodiment 34 or 35, wherein the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

[0158] 37. The kit or composition of embodiment 26 or 27, wherein the immunogenic cell death inducer is a KRAS G12D inhibitor.

[0159] 38. The kit or composition of embodiment 37, wherein the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000, or a pharmaceutically acceptable salt thereof.

[0160] 39. The kit or composition of embodiment 37 or 38, wherein the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

[0161] 40. The kit or composition of any one of embodiments 26 to 39, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

[0162] 41. The immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and the anti-PD-1 / PD-L1 antibody is selected from the group consisting of pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, and avelumab. umab, Atezolizumab, Camrelizumab, Sintilimab, Cemiplimab, Envafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.

[0163] 42. The kit or composition according to any one of embodiments 26 to 40, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and further wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.

[0164] 43. The immune checkpoint inhibitor is a TIGIT antibody, and further, the TIGIT antibody is selected from the group consisting of osipelimab (Ociperlimab / BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, belrestotug, etigilimab, and ONO-46. 86, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.

[0165] 44. The kit or composition of embodiment 26, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is lurbinectedin, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0166] 45. The kit or composition of embodiment 26, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0167] 46. ​​The kit or composition of embodiment 26, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0168] 47. The kit or composition described in embodiment 26, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is a TIGIT antibody.

[0169] 48. A kit or composition according to any one of embodiments 26 to 47, wherein the composition is used in medicine.

[0170] 49. The drug is used to treat tumors, and the tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine tumor, ovarian cancer, salivary gland cancer, and spindle cell carcinoma. 49. The kit or composition of embodiment 48, wherein the cancer is a metastatic tumor of any of the following: anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or a hematopoietic malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, or pancreatic cancer.

[0171] 50. The kit or composition of embodiment 49, wherein the tumor is lung cancer, colon cancer (including large bowel cancer), or breast cancer.

[0172] 51. A method for treating a tumor in a subject, comprising administering to the subject therapeutically effective amounts of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0173] 52. The method of embodiment 51, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945 or a pharmaceutically acceptable salt thereof, more preferably IN10018 or a pharmaceutically acceptable salt thereof, particularly IN10018 tartrate, and the structure of IN10018 is as follows: [ka]

[0174] 53. The method of embodiment 51 or 52, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II.

[0175] 54. The method of embodiment 53, wherein the inhibitor of RNA polymerase II is lurbinectedin, SEL-120, or a pharmaceutically acceptable salt thereof.

[0176] 55. The method of embodiment 53 or 54, wherein the inhibitor of RNA polymerase II is lurbinectedin.

[0177] 56. The method of embodiment 51 or 52, wherein the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

[0178] 57. The method of embodiment 56, wherein the ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib, or a pharmaceutically acceptable salt thereof, in particular, crizotinib, entrectinib, or a pharmaceutically acceptable salt thereof.

[0179] 58. The method of embodiment 56 or 57, wherein the ALK / ROS1 inhibitor is crizotinib or a pharmaceutically acceptable salt thereof.

[0180] 59. The method of embodiment 51 or 52, wherein the immunogenic cell death inducer is a KRAS G12C inhibitor.

[0181] 60. The method of embodiment 59, wherein the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, Sotorasib (sotorasib / AMG510), Adagrasib (MRTX849), GDC-6036 or a pharmaceutically acceptable salt thereof, in particular D-1553, Sotorasib (sotorasib / AMG510) or a pharmaceutically acceptable salt thereof.

[0182] 61. The method of embodiment 59 or 60, wherein the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

[0183] 62. The method of embodiment 51 or 52, wherein the immunogenic cell death inducer is a KRAS G12D inhibitor.

[0184] 63. The method of embodiment 62, wherein the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000, or a pharmaceutically acceptable salt thereof.

[0185] 64. The method of embodiment 62 or 63, wherein the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

[0186] 65. The method of any one of embodiments 51 to 64, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

[0187] 66. The immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and further, the anti-PD-1 / PD-L1 antibody is selected from the group consisting of pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, abet 66. The method of embodiment 65, wherein the therapeutic agent is Avelumab, Atezolizumab, Camrelizumab, Sintilimab, Cemiplimab, Envafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181.

[0188] 67. The method of embodiment 65, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and further wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.

[0189] 68. The method of embodiment 65, wherein the immune checkpoint inhibitor is a TIGIT antibody, and further wherein the TIGIT antibody is osipelimab (Ociperlimab / BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, belrestotug, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321.

[0190] 69. The method of embodiment 51, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is lurbinectedin, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0191] 70. The method of embodiment 51, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0192] 71. The method of embodiment 51, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0193] 72. The method of embodiment 51, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, particularly, the immune checkpoint inhibitor is a TIGIT antibody.

[0194] 73. The method of any one of embodiments 51 to 72, wherein the FAK inhibitor, the immunogenic cell death inducer and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

[0195] 74. The tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine tumor, ovarian cancer, salivary gland cancer, metastatic tumors from spindle cell carcinoma, undifferentiated large cell carcinoma, The method according to any one of embodiments 51 to 73, wherein the cancer is selected from the group consisting of thyroid cancer, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematopoietic malignancies, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, or pancreatic cancer.

[0196] 75. The method of embodiment 74, wherein the tumor is breast cancer, ovarian cancer, or colon cancer (including colorectal cancer).

[0197] 76. A FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor for use in a method for treating a tumor by increasing immunogenic cell death in a subject, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0198] 77. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 76, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945 or a pharmaceutically acceptable salt thereof, more preferably IN10018 or a pharmaceutically acceptable salt thereof, particularly IN10018 tartrate, and the structure of IN10018 is as follows: [ka]

[0199] 78. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 76 or 77, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II.

[0200] 79. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 78, wherein the inhibitor of RNA polymerase II is lurbinectedin, SEL-120 or a pharmaceutically acceptable salt thereof.

[0201] 80. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor of embodiment 78 or 79, wherein the inhibitor of RNA polymerase II is lurbinectedin.

[0202] 81. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 76 or 77, wherein the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

[0203] 82. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 81, wherein the ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib or a pharmaceutically acceptable salt thereof, in particular crizotinib, entrectinib or a pharmaceutically acceptable salt thereof.

[0204] 83. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 81 or 82, wherein the ALK / ROS1 inhibitor is crizotinib or a pharmaceutically acceptable salt thereof.

[0205] 84. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 76 or 77, wherein the immunogenic cell death inducer is a KRAS G12C inhibitor.

[0206] 85. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 84, wherein the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, Sotorasib (sotorasib / AMG510), Adagrasib (MRTX849), GDC-6036 or a pharmaceutically acceptable salt thereof, in particular D-1553, Sotorasib (sotorasib / AMG510) or a pharmaceutically acceptable salt thereof.

[0207] 86. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 84 or 85, wherein the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

[0208] 87. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 76 or 77, wherein the immunogenic cell death inducer is a KRAS G12D inhibitor.

[0209] 88. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 87, wherein the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000 or a pharmaceutically acceptable salt thereof.

[0210] 89. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 87 or 88, wherein the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

[0211] 90. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to any one of embodiments 76 to 89, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

[0212] 91. The immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and further, the anti-PD-1 / PD-L1 antibody is selected from the group consisting of pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, and atezolizumab. 91. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to any one of embodiments 76 to 90, wherein the FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor is atezolizumab, camrelizumab, sintilimab, cemiplimab, envafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.

[0213] 92. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to any one of embodiments 76 to 90, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and further wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.

[0214] 93. The immune checkpoint inhibitor is a TIGIT antibody, and further, the TIGIT antibody is selected from the group consisting of osiperlimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, belrestotug, etigilimab, ONO-4686, JS-006, and AZD 91. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor of any one of embodiments 76 to 90, wherein the FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor is IL-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.

[0215] 94. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to embodiment 76, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is lurbinectedin, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0216] 95. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to embodiment 76, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0217] 96. The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to embodiment 76, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0218] 97. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor described in embodiment 76, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is a TIGIT antibody.

[0219] 98. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor described in any one of embodiments 76 to 97, wherein the FAK inhibitor, the immunogenic cell death inducer and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

[0220] 99. The tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine tumor, ovarian cancer, salivary gland cancer, metastatic tumors from spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-small cell carcinoma, ovarian cancer, salivary gland cancer, ovarian ... The FAK inhibitor, immunogenic cell death inducer, and immune checkpoint inhibitor according to any one of embodiments 76 to 98, which are Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematopoietic malignancies, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, or pancreatic cancer.

[0221] 100. The FAK inhibitor, immunogenic cell death inducer and immune checkpoint inhibitor according to embodiment 99, wherein the tumor is lung cancer, colon cancer (including colorectal cancer) or breast cancer.

[0222] 101. A method for treating a tumor by increasing immunogenic cell death in a subject, comprising administering to the subject therapeutically effective amounts of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0223] 102. The method of embodiment 101, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945 or a pharmaceutically acceptable salt thereof, more preferably IN10018 or a pharmaceutically acceptable salt thereof, particularly IN10018 tartrate, and the structure of IN10018 is as follows: [ka]

[0224] 103. The method of embodiment 101 or 102, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II.

[0225] 104. The method of embodiment 103, wherein the inhibitor of RNA polymerase II is lurbinectedin, SEL-120, or a pharmaceutically acceptable salt thereof.

[0226] 105. The method of embodiment 103 or 104, wherein the inhibitor of RNA polymerase II is lurbinectedin.

[0227] 106. The method of embodiment 101 or 102, wherein the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

[0228] 107. The method according to embodiment 106, wherein the ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib or a pharmaceutically acceptable salt thereof, in particular, crizotinib, entrectinib or a pharmaceutically acceptable salt thereof.

[0229] 108. The method of embodiment 106 or 107, wherein the ALK / ROS1 inhibitor is crizotinib or a pharmaceutically acceptable salt thereof.

[0230] 109. The method of embodiment 101 or 102, wherein the immunogenic cell death inducer is a KRAS G12C inhibitor.

[0231] 110. The method of embodiment 109, wherein the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, Sotorasib (sotorasib / AMG510), Adagrasib (MRTX849), GDC-6036 or a pharmaceutically acceptable salt thereof, in particular D-1553, Sotorasib (sotorasib / AMG510) or a pharmaceutically acceptable salt thereof.

[0232] 111. The method of embodiment 109 or 110, wherein the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

[0233] 112. The method of embodiment 101 or 102, wherein the immunogenic cell death inducer is a KRAS G12D inhibitor.

[0234] 113. The method of embodiment 112, wherein the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000, or a pharmaceutically acceptable salt thereof.

[0235] 114. The method of embodiment 112 or 113, wherein the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

[0236] 115. The method of any one of embodiments 101 to 114, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

[0237] 116, the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and further, the anti-PD-1 / PD-L1 antibody is selected from the group consisting of pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, abet The method of embodiment 115, wherein the therapeutic agent is Avelumab, Atezolizumab, Camrelizumab, Sintilimab, Cemiplimab, Envafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181.

[0238] 117. The method of embodiment 115, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and further wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.

[0239] 118. The method of embodiment 115, wherein the immune checkpoint inhibitor is a TIGIT antibody, and further wherein the TIGIT antibody is osipelimab (Ociperlimab / BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, belrestotug, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321.

[0240] 119. The method of embodiment 101, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is lurbinectedin, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0241] 120. The method of embodiment 101, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0242] 121. The method of embodiment 101, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0243] 122. The method of embodiment 101, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is a TIGIT antibody.

[0244] 123. The method of any one of embodiments 101 to 122, wherein the FAK inhibitor, the immunogenic cell death inducer and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

[0245] 124. The tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine tumor, ovarian cancer, salivary gland cancer, metastatic tumors from spindle cell carcinoma, undifferentiated large cell carcinoma, The method according to any one of embodiments 101 to 123, wherein the cancer is selected from the group consisting of thyroid cancer, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematopoietic malignancies, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, or pancreatic cancer.

[0246] 125. The method of embodiment 124, wherein the tumor is lung cancer, colon cancer (including colorectal cancer), or breast cancer.

[0247] 126. Use of a FAK inhibitor in the manufacture of a drug for treating a tumor in a subject, wherein the FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor are administered to the subject, and the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0248] 127. Use of an immunogenic cell death inducer in the manufacture of a drug for treating a tumor in a subject, comprising administering to the subject a FAK inhibitor, the immunogenic cell death inducer, and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0249] 128. Use of an immune checkpoint inhibitor in the manufacture of a drug for treating a tumor in a subject, comprising administering to the subject a FAK inhibitor, an immunogenic cell death inducer, and the immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0250] 129. Use of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor in the manufacture of a combination drug for treating a tumor, wherein the immunogenic cell death inducer is an RNA polymerase II inhibitor, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0251] 130. Use of a FAK inhibitor together with an immunogenic cell death inducer and an immune checkpoint inhibitor in the manufacture of a combination drug for treating tumors, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0252] 131. Use of an immunogenic cell death inducer in the manufacture of a combination drug for treating tumors together with a FAK inhibitor and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0253] 132. Use of an immune checkpoint inhibitor together with a FAK inhibitor and an immunogenic cell death inducer in the manufacture of a combination drug for treating tumors, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0254] 133. Use of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor in combination to manufacture a drug for treating a tumor, wherein the immunogenic cell death inducer is an RNA polymerase II inhibitor, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0255] 134. Use of a FAK inhibitor in the manufacture of a drug for treating tumors in combination with an immunogenic cell death inducer and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0256] 135. Use of an immunogenic cell death inducer in the manufacture of a drug for treating tumors in combination with a FAK inhibitor and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0257] 136. Use of an immune checkpoint inhibitor in combination with a FAK inhibitor and an immunogenic cell death inducer in the manufacture of a drug for treating tumors, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

[0258] 137. The use according to any one of embodiments 126 to 136, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof, more preferably IN10018 or a pharmaceutically acceptable salt thereof, in particular IN10018 tartrate, and the structure of IN10018 is as follows: [ka]

[0259] 138. The use according to any one of embodiments 126 to 137, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II.

[0260] 139. The use according to embodiment 138, wherein the inhibitor of RNA polymerase II is lurbinectedin, SEL-120 or a pharmaceutically acceptable salt thereof.

[0261] 140. The use according to embodiment 138 or 139, wherein the inhibitor of RNA polymerase II is lurbinectedin.

[0262] 141. The use according to any one of embodiments 126 to 137, wherein the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

[0263] 142. The use according to embodiment 141, wherein the ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib or a pharmaceutically acceptable salt thereof, in particular crizotinib, entrectinib or a pharmaceutically acceptable salt thereof.

[0264] 143. The use according to embodiment 141 or 142, wherein the ALK / ROS1 inhibitor is crizotinib or a pharmaceutically acceptable salt thereof.

[0265] 144. The use of any one of embodiments 126 to 137, wherein the immunogenic cell death inducer is a KRAS G12C inhibitor.

[0266] 145. The use according to embodiment 144, wherein the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, Sotorasib (sotorasib / AMG510), Adagrasib (MRTX849), GDC-6036 or a pharmaceutically acceptable salt thereof, in particular D-1553, Sotorasib (sotorasib / AMG510) or a pharmaceutically acceptable salt thereof.

[0267] 146. The use according to embodiment 144 or 145, wherein the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

[0268] 147. The use according to any one of embodiments 126 to 137, wherein the immunogenic cell death inducer is a KRAS G12D inhibitor.

[0269] 148. The use according to embodiment 147, wherein the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000 or a pharmaceutically acceptable salt thereof.

[0270] 149. The use according to embodiment 147 or 148, wherein the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

[0271] 150. The use of any one of embodiments 126 to 149, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

[0272] 151, the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and further, the anti-PD-1 / PD-L1 antibody is selected from the group consisting of pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, abet The use of embodiment 150, wherein the agent is Avelumab, Atezolizumab, Camrelizumab, Sintilimab, Cemiplimab, Envafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.

[0273] 152. The use described in embodiment 150, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and further wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.

[0274] 153. The use of embodiment 150, wherein the immune checkpoint inhibitor is a TIGIT antibody, and further wherein the TIGIT antibody is osipelimab (Ociperlimab / BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, belrestotug, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321.

[0275] 154. The use according to any one of embodiments 126 to 136, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is lurbinectedin, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0276] 155. The use of any one of embodiments 126 to 136, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0277] 156. The use of any one of embodiments 126 to 136, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

[0278] 157. The use according to any one of embodiments 126 to 136, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is a TIGIT antibody.

[0279] 158. The use of any one of embodiments 126 to 157, wherein the FAK inhibitor, the immunogenic cell death inducer and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

[0280] 159, The tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine tumor, ovarian cancer, salivary gland cancer, metastatic tumor from spindle cell carcinoma, undifferentiated large cell carcinoma The use according to any one of embodiments 126 to 158, wherein the cancer is selected from the group consisting of thyroid cancer, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematopoietic malignancies, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, or pancreatic cancer.

[0281] 160. The use of embodiment 159, wherein the tumor is lung cancer, colon cancer (including colorectal cancer), or breast cancer.

[0282] Example The following examples are provided to further illustrate the present invention, and it should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0283] In the following examples, experimental methods for which specific conditions are not specified may be carried out according to standard conditions or conditions recommended by the manufacturer. All experimental materials and reagents used in the following examples are commercially available unless otherwise specified.

[0284] The meanings of the abbreviations used in the examples are as follows: English abbreviation: Chinese name siRNA: small interfering RNA DMSO: dimethyl sulfoxide COMBO: Combined or combined use HMGB1: high-mobility group box protein 1 AAALAC: Association for Assessment and Accreditation of Laboratory Animal Care International IACUC: Laboratory Animal Care and Use Committee SPF: Special Pathogen Free BIW : Twice a week BID: Twice a day QD: Once a day BW: Weight EDTA: Ethylenediaminetetraacetic acid GLP: Good Laboratory Practice (GLP) for non-clinical trials related to drug safety po: intragastric administration iv: intravenous administration ip: intraperitoneal injection DPBS: Dulbecco's phosphate buffer solution DDH2O: double distilled water RT: room temperature SEM: standard error TGI: Tumor growth inhibition rate TV: tumor volume TW: tumor weight FBS: fetal bovine serum PBS: Phosphate buffer solution MC: Methylcellulose CO2: Carbon dioxide CRT: Calreticulin Annexin-V-FITC: Fluorescein isothiocyanate-labeled annexin PI: propidium iodide

[0285] Example 1: Synergistic effect of IN10018 and lurbinectedin in colon cancer CT26 cells Mouse colon carcinoma CT26 cells (Chinese Academy of Sciences Institute of Cellular Biology) were cultured in RPMI-1640 (Shanghai Yuanpei, Catalog No. L210KJ, Lot No. F210916) with 10% FBS (Gibco, Catalog No. 10099-141c, Lot No. 2158737cp) and passaged twice. When the cells were in good condition, they were plated at 3,000 cells / well in 96-well plates. After 24 hours of cell proliferation, medium containing lurbinectedin (DC Chemicals, Catalog No. DC12502, Lot No. DC1250203) was added. Ten drug-working concentrations were established, with the initial concentration at 0.1 μM and diluted 4-fold. The final concentration served as a control, representing the drug concentration at 0. Triplicate wells were set for each drug concentration. Separate cell groups were then established using the same drug concentrations as above. The difference is that 6 μM IN10018 was added to each well, the drugs were mixed, and the mixture was incubated at 37° C. in a 5% CO 2 incubator for 72 hours.

[0286] After 72 hours of drug exposure, the cells were observed under a microscope, and 10 μl of CCK8 detection reagent (Cellorlab, catalog number: CX001M, lot number: 2571100) was added to each well. After incubation at 37°C in a 5% CO2 incubator for 2 to 4 hours, the well plate was read at OD450 (chemiluminescence method) using a microplate reader.

[0287] The analysis results showed that the IC50 of the lurbinectedin group was 0.71 nM, and the IC50 of the lurbinectedin + 6 μM IN10018 group was 0.30 nM. The IC50 of the IN10018-containing group was lower than the IC50 of the IN10018-free group, indicating that the therapeutic effect of the dual-drug combination treatment group was higher than that of the single-drug treatment group, as shown in Figure 1.

[0288] Example 2: Study of IN10018 and lurbinectedin in colon cancer CT26 cells Mouse colon carcinoma CT26 cells (Institute of Cellular Biology, Chinese Academy of Sciences) were cultured in RPMI-1640 (Shanghai Yuanpei, catalog number: L210KJ, lot number: F210916) + 10% FBS (Gibco, catalog number: 10099-141c, lot number: 2158737cp) and passaged twice. When the cells were in good condition, the culture medium was placed in a 24-well plate. Twenty-four hours after cell proliferation, the cells were divided into four groups: Group 1 (control group) with medium added; Group 2 (IN10018 at a concentration of 5 μM); Group 3 (lurbinectedin (DC Chemicals, catalog number: DC12502, lot number: DC1250203) at a concentration of 0.00142 μM); and Group 4 (IN10018 (5 μM) and lurbinectedin (0.00142 μM) combined). The drugs were mixed and cultured at 37°C in a 5% CO incubator for 48 hours.

[0289] After 48 hours of drug treatment, cells were observed under a microscope and photographed. Cells were then harvested for flow analysis. After washing twice with flow cytometry buffer (PBS + 2% FBS), 0.5 μl of AF647 anti-calreticulin antibody (Abcam, catalog number: ab196159, lot number: CR33676773) was added to each well, mixed thoroughly, and incubated at 4°C for 20 minutes in the dark. After 20 minutes, cells were washed twice with flow cytometry buffer (PBS + 2% FBS). Using an apoptosis detection kit (Beyotime, catalog number: CL062L, lot number: 021921210811), 195 μl of annexin-V-FITC conjugate was added, gently mixed, and then 5 μl of annexin-V-FITC antibody was added and gently mixed. 10 μl of PI dye was added, mixed gently, and incubated at room temperature in the dark for 15 minutes before analysis on a flow cytometer.

[0290] Microscopic observation of the cells revealed poor cell condition in the lurbinectedin monotherapy group and the dual-drug combination group, with the dual-drug combination group experiencing the poorest cell condition and significant cell death, and good cell condition in the control and IN10018 groups (see Figure 2 for details). The results showed that the dual-drug combination group had higher CRT and Annexin V positivity rates than the single-drug group (see Figure 3 for details).

[0291] Example 3: Synergistic effect of IN10018 and MRTX1133 in colon cancer CT26 cells Mouse colon carcinoma CT26 cells (Chinese Academy of Sciences Institute of Cellular Biology) were cultured in RPMI-1640 (Shanghai Yuanpei, Catalog No. L210KJ, Lot No. F210916) + 10% FBS (Gibco, Catalog No. 10099-141c, Lot No. 2158737cp) and passaged twice. When the cells were in good condition, they were plated at 3,000 cells / well in a 96-well plate. After 24 hours of cell proliferation, medium containing MRTX1133 (Shanghai Chaolun Chemical Technology Center, Catalog No. P2621928-55-8, Lot No. 131005) was added. Ten drug concentrations were established, with the initial concentration being 30 μM, diluted 5-fold, and the final concentration serving as a control (0 μM). Three composite wells were set up for each drug concentration. Separate cell groups were then established using the same drug concentrations as above. The difference is that 5 μM IN10018 is added to each well, the drugs are mixed, and the plates are incubated at 37° C. in a 5% CO 2 incubator for 72 hours.

[0292] After 72 hours of drug exposure, cells were observed under a microscope. 10 μl of CCK8 detection reagent (Cellorlab, Catalog No. CX001M, Lot No. 2571100) was added to each well and incubated for 2-4 hours in a 37°C, 5% CO2 incubator. The OD450 readings were then measured using a microplate reader (chemiluminescence method). The IC50 for the MRTX1133 group was 0.28 μM, while the IC50 for the MRTX1133 + 5 μM IN10018 group was 0.02 μM. The IC50 for the IN10018-containing group was significantly lower than that for the IN10018-free group, indicating that the therapeutic effect of the dual-drug treatment group was greater than that of the single-drug treatment group, as shown in Figure 4.

[0293] Example 4: Study of IN10018 and MRTX1133 in colon cancer CT26 cells Murine colon carcinoma CT26 cells (Chinese Academy of Sciences Institute of Cellular Biology) were cultured in RPMI-1640 medium (Shanghai Yuanpei, Catalog Number: L210KJ, Lot Number: F210916) with 10% FBS (Gibco, Catalog Number: 10099-141c, Lot Number: 2158737cp) and passaged twice. When cells were in good condition, the culture medium was plated in a 24-well plate. After 24 hours of cell proliferation, four groups were established: Group 1 (control) with medium; Group 2 (IN10018 at 5 μM; Group 3 (MRTX1133) at 6 μM (Shanghai Chaolan Chemical Technology Center, Catalog Number: P2621928-55-8, Lot Number: 131005); and Group 4 (IN10018 (5 μM) and MRTX1133 (6 μM) combined). The drugs were mixed and cultured at 37°C in a 5% CO2 incubator for 48 hours.

[0294] After 48 hours of drug exposure, cells were observed under a microscope and photographed. Cells were then harvested for flow analysis. After washing twice with flow cytometry buffer (PBS + 2% FBS), 0.5 μl of AF647 anti-calreticulin antibody (Abcam, catalog number: ab196159, lot number: CR33676773) was added to each well, mixed thoroughly, and incubated at 4°C for 20 minutes in the dark. After 20 minutes, cells were washed twice with flow cytometry buffer (PBS + 2% FBS). Using an apoptosis detection kit (Beyotime, catalog number: CL062L, lot number: 021921210811), 195 μl of annexin-V-FITC conjugate was added, and the cells were gently mixed. Then, 5 μl of annexin-V-FITC antibody was added, gently mixed, and 10 μl of PI dye was added and mixed. The cells were incubated at room temperature in the dark for 15 minutes, and then analyzed by flow cytometer.

[0295] Microscopic observation of the cells revealed that the MRTX1133 single-agent group and the dual-drug combination group were in poor cell condition, with the dual-drug combination group experiencing the poorest cell condition and significant cell death, while the control and IN10018 groups were in good cell condition (see Figure 5 for details). The results showed that the dual-drug combination group had higher CRT and Annexin V positivity rates than the single-drug group (see Figure 6 for details).

[0296] Example 5: Synergistic effect of IN10018 and MRTX1133 in lung cancer KPL cells Mouse lung cancer KPL cells (Chinese Academy of Sciences Institute of Cellular Biology) were cultured in RPMI-1640 (Shanghai Yuanpei, Catalog No. L210KJ, Lot No. F210916) + 10% FBS (Gibco, Catalog No. 10099-141c, Lot No. 2158737cp) and passaged twice. When the cells were in good condition, they were plated at 3,000 cells / well in 96-well plates. After 24 hours of cell proliferation, medium containing MRTX1133 (Shanghai Chaolun Chemical Technology Center, Catalog No. P2621928-55-8, Lot No. 131005) was added. Ten drug concentrations were established, with the initial concentration at 30 μM and diluted 5-fold. The final concentration served as a control, representing the drug concentration at 0. Three composite wells were set up for each drug concentration. Separate cell groups were then established using the same drug concentrations as above. The difference is that 10 μM IN10018 is added to each well, the drugs are mixed, and the mixture is incubated at 37° C. in a 5% CO 2 incubator for 72 hours.

[0297] After 72 hours of drug exposure, the cells were observed under a microscope, and 10 μl of CCK8 detection reagent (Cellorlab, catalog number: CX001M, lot number: 2571100) was added to each well. After incubation at 37°C in a 5% CO2 incubator for 2 to 4 hours, the well plate was read at OD450 (chemiluminescence method) using a microplate reader.

[0298] According to the analysis results, the IC50 of the MRTX1133 group was 1.76 μM, and the IC50 of the MRTX1133 + 10 μM IN10018 group was 0.008 μM. The IC50 of the IN10018-containing group was significantly smaller than the IC50 of the IN10018-free group, which indicates that the therapeutic effect of the dual-drug combination treatment group was higher than that of the single-drug treatment group, as shown in Figure 7.

[0299] Example 6: Study of IN10018 and MRTX1133 in lung cancer KPL cells Mouse lung cancer KPL cells (Institute of Cellular Biology, Chinese Academy of Sciences) were cultured in RPMI-1640 (Shanghai Yuanpei, catalog number: L210KJ, lot number: F210916) + 10% FBS (Gibco, catalog number: 10099-141c, lot number: 2158737cp) and passaged twice. When the cells were in good condition, the culture medium was placed in a 24-well plate. After 24 hours of cell proliferation, four groups were established: Group 1 was the control group, with medium added; Group 2 was IN10018 at a concentration of 10 μM; Group 3 was MRTX1133 (Shanghai Chaolan Chemical Technology Center, Catalog Number: P2621928-55-8, Lot Number: 131005) at a concentration of 15 μM; and Group 4 was a combination of IN10018 (10 μM) and MRTX1133 (15 μM). The drugs were mixed and cultured at 37 °C in a 5% CO incubator for 48 hours.

[0300] After 48 hours of drug exposure, cells were observed under a microscope and photographed. Cells were then harvested for flow analysis. After washing twice with flow cytometry buffer (PBS + 2% FBS), 0.5 μl of AF647 anti-calreticulin antibody (Abcam, catalog number: ab196159, lot number: CR33676773) was added to each well, mixed thoroughly, and incubated at 4°C for 20 minutes in the dark. After 20 minutes, cells were washed twice with flow cytometry buffer (PBS + 2% FBS). Using an apoptosis detection kit (Beyotime, catalog number: CL062L, lot number: 021921210811), 195 μl of annexin-V-FITC conjugate was added, and the cells were gently mixed. Then, 5 μl of annexin-V-FITC antibody was added, gently mixed, and 10 μl of PI dye was added and mixed. The cells were incubated at room temperature in the dark for 15 minutes, and then analyzed by flow cytometer.

[0301] Microscopic observation of the cells revealed that the MRTX1133 single-agent group and the dual-drug combination group were in poor cell condition, with the dual-drug combination group experiencing the poorest cell condition and significant cell death, while the control and IN10018 groups were in good cell condition (see Figure 8 for details). The results showed that the dual-drug combination group had higher CRT and Annexin V positivity rates than the single-agent group (see Figure 9 for details).

[0302] Example 7: Study of targeting immunogenic cell death of mouse colon cancer CT26 cells by crizotinib and IN10018 The compound information is shown in Table 1.

[0303] [Table 1]

[0304] Table 2 shows the main reagents used in the experiment.

[0305] [Table 2]

[0306] The experimental design is shown in Table 3.

[0307] [Table 3]

[0308] Cell culture: CT26 cells were cultured in vitro in monolayers in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in 5% CO2. They were passaged 2-3 times per week by routine digestion with trypsin. When cells were in the exponential growth phase and reached 80-90% confluence, they were harvested and plated.

[0309] CT26 cells were digested with trypsin, harvested, and counted. Based on the counting results, the cells were diluted with RPMI-1640 + 10% FBS to a concentration of 50,000 cells per milliliter and plated into a 24-well cell culture plate, with 1 ml of cell suspension (50,000 cells) plated into each well. After plating, the cells were cultured in a 37°C, 5% CO2 incubator.

[0310] A test compound is added, 24 hours after plating, the test compounds IN10018 and crizotinib were added to different wells, respectively, and the group divisions and drug concentrations are shown in Table 3.

[0311] Cells were collected and analyzed by flow cytometry. After the drug was allowed to act for 48 hours, the cells were photographed under a microscope, digested with trypsin, and collected for flow cytometry staining.

[0312] After washing the cells twice with flow cytometry buffer (DPBS + 2% FBS), each group of cells was divided into two equal portions. 0.5 μL of AF647 Anti-Calreticulin Antibody was added to each well of one portion, mixed thoroughly, and incubated at 4°C in the dark for 20 minutes. After washing once with flow cytometry buffer, 195 μL of Annexin-V-FITC binding buffer was added, and the cells were gently mixed thoroughly. 5 μL of Annexin-V-FITC antibody was added, mixed thoroughly again, and 10 μL of PI dye was added and mixed thoroughly. The mixture was then incubated at room temperature in the dark for 15 minutes, after which flow cytometry analysis was performed.

[0313] Data analysis: After the experiment was completed, the cell positivity rate was analyzed using Flowjo (V10) software.

[0314] Test Results: After 48 hours of drug exposure, the cells were examined under a microscope. Cell death was evident in the crizotinib monotherapy group, the most pronounced in the combination therapy group, and high cell activity in the control and IN10018 groups. Flow cytometry analysis showed that the CRT and Annexin-V positivity rates in the combination therapy group were higher than in the single-drug group. Related detection results are shown in Figure 10.

[0315] Example 8: In vivo pharmacodynamic study of test drugs in a BALB / c mouse model with subcutaneous allograft tumors of murine colon carcinoma CT26-KRAS G12C cells Test materials: Species: Mouse, Breed: BALB / c, Age and Weight: 6-8 weeks, Weight: 18-22g, Gender: Female, Quantity: 49 (excluding mice remaining after group division) Supplier: Shanghai Lingcheng Biotechnology Co., Ltd. After purchase, the animals were housed in an experimental environment for 3–7 days before the experiment began. Animals were housed in individually ventilated cages (3–4 per cage) in an SPF animal room. The animal information card for each cage should clearly indicate the number of animals in the cage, their sex, breed, date and time of receipt, dosing scheme, experiment number, group, and start date of the experiment. All cages, bedding, and drinking water had to be sterilized before use. Cages, food, and drinking water were changed twice weekly. The housing environment and lighting conditions were as follows: temperature: 20–26°C, humidity: 40–70%, photoperiod: 12 hours on, 12 hours off (lights on at 8:00 AM, lights off at 8:00 PM), and polycarbonate cages measuring 300 mm x 180 mm x 150 mm. Corn cob bedding was used and changed twice weekly. Food: Experimental animals will have free access to (radiation sterilized, dry particulate food) throughout the entire experimental phase. Drinking water: Experimental animals will have free access to sterile water. Animal labeling: Experimental animals will be ear-marked.

[0316] Information on the test and control substances is shown in Table 4.

[0317] [Table 4] Note: (INX0082 is a PD1 antibody)

[0318] Experimental methods and steps: Murine colon carcinoma CT26-KRAS G12C cells were cultured in vitro in monolayers in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin, streptomycin, and amphotericin B at 37°C in a 5% CO2 incubator. Cells were passaged twice weekly using pancreatin-EDTA digestion. When the cell saturation reached 80%-90% and the required number of cells was reached, the cells were harvested, counted, and inoculated.

[0319] 0.1 mL (0.3 × 10 6CT26-KRAS G12C cells were inoculated subcutaneously into the right hindquarters of each mouse, resulting in a tumor with an average volume of approximately 55 mm 3 If this is the case, the subjects will be divided into groups and administered the drugs. The group information is shown in Table 5.

[0320] [Table 5] Note: 1. N: number of mice in each group. 2. Dosage volume: 10 μl / g according to the body weight of the mouse. If the body weight loss exceeds 15%, the administration scheme should be adjusted accordingly.

[0321] The preparation of the test substances is shown in Table 6.

[0322] Test substance preparation method [Table 6] NOTE: It is necessary to mix the drug thoroughly before administering it to the animals.

[0323] Routine observation of laboratory animals: The health and mortality of the animals were monitored daily, and routine examinations included observing tumor growth and the effects of drug treatment on the animals' daily behavior, such as behavior, food and water intake (visual observation only), weight change (weight was measured three times a week), external signs, or other abnormalities. The number of animal deaths and side effects within groups were recorded based on the number of animals in each group.

[0324] Tumor Measurements and Laboratory Parameters: Tumor diameters were measured three times a week using a caliper. The formula for calculating tumor volume was V = 0.5 × a × b 2 where a and b represent the long and short diameters of the tumor, respectively.

[0325] The tumor inhibitory effect of the compound was evaluated by TGI (%) or relative tumor growth rate T / C (%). Relative tumor growth rate T / C (%) = T RTV / C RTV ×100%(T RTV :Treatment group RTV, C RTVRTV: negative control group). Based on the tumor measurement results, the relative tumor volume (RTV) was calculated using the formula: RTV = V t / V0, where V0 is the mean tumor volume measured at the time of group administration (i.e., D0), and V t is the mean tumor volume at a particular measurement, and T RTV and C RTV Data from the same day was used as the

[0326] TGI (%) reflects the tumor growth inhibition rate: TGI (%) = [1 - (mean tumor volume at the end of treatment for a treatment group - mean tumor volume at the start of treatment for that treatment group) / (mean tumor volume at the end of treatment for the vehicle control group - mean tumor volume at the start of treatment for the vehicle control group)] x 100%.

[0327] Statistical analysis: Statistical analysis included the mean and standard error (SEM) of tumor volume for each group at each time point (specific data are shown in Table 7). Statistical analysis was performed based on the tumor volume data on day 19 after administration to evaluate differences between groups. Comparisons between two groups were analyzed using a t-test, and comparisons between three or more groups were analyzed using one-way ANOVA. If there was a significant difference in the F value, it should be verified using the Games-Howell method. If there was no significant difference in the F value, it should be analyzed using the Dunnett (2-sided) method. All data were analyzed using SPSS 17.0. A p<0.05 was considered significant.

[0328] Test Results: The body weight of the experimental animals was used as a reference index to indirectly measure the toxicity of the drug. In this model, no significant weight loss was observed in any of the treatment groups (as shown in Figure 11), and no morbidity or mortality was observed in the mice.

[0329] The effect of the test substance on the body weight of female BALB / c mice with subcutaneous allograft tumors of mouse colon cancer CT26-KRAS G12C cells is shown in Figures 11 and 12.

[0330] In this experiment, the in vivo efficacy of the test substances administered alone and in combination was evaluated in a mouse colon cancer CT26-KRAS G12C allograft tumor model. After 19 days of administration, the vehicle control group showed a mean tumor volume of 1746 mm 3 The mean tumor volume in the group administered with test substance D-1553 (5 mg / kg) was 995 mm 3 (T / C was 57.0%, TGI was 44.4%, p value was 0.251), and it had a certain tumor inhibitory effect compared to the solvent control group. The group administered with the test substance IN10018 (25 mg / kg) had a mean tumor volume of 1352 mm 3 (T / C was 74.7%, TGI was 23.4%, p value was 0.938), and it had no tumor inhibitory effect compared to the vehicle control group. The group administered the test substance INX0082 (10 mg / kg) had a mean tumor volume of 920 mm 3 (T / C was 54.7%, TGI was 48.9%, p value was 0.348), and compared with the solvent control group, it also had a certain tumor inhibitory effect. The group administered the test substances D-1553 (5 mg / kg) and IN10018 (25 mg / kg) in combination had a mean tumor volume of 650 mm 3 (T / C was 36.2%, TGI was 64.8%, p-value was 0.063), demonstrating a better tumor inhibitory effect than the vehicle control group. The group administered the test substances D-1553 (5 mg / kg) and INX0082 (10 mg / kg) in combination had a mean tumor volume of 668 mm 3 (T / C was 39.2%, TGI was 63.8%, p-value was 0.053), which showed similarly good tumor inhibitory activity compared to the vehicle control group. The group administered the test substances D-1553 (5 mg / kg), IN10018 (25 mg / kg), and INX0082 (10 mg / kg) in combination had a mean tumor volume of 412 mm 3 (T / C was 22.9%, TGI was 78.9%, p-value was 0.016), and it had a significant tumor inhibitory effect compared to the vehicle control group, as shown in Table 7 and Figure 13.

[0331] [Table 7] Note: a, Mean ± SEM, n = 7. b, p (One-way ANOVA) values ​​were calculated based on tumor volume.

[0332] Example 9: Study of in vivo antitumor efficacy in a BALB / c mouse subcutaneous allograft tumor model of mouse colon cancer CT26 cells when combined with test substance MRTX1133, anti-mouse TIGIT antibody, and IN10018 Test materials: Information on the experimental animals is shown in Table 8.

[0333] [Table 8]

[0334] The rearing environment is shown in Table 9.

[0335] [Table 9]

[0336] Test substance information is shown in Table 10.

[0337] [Table 10]

[0338] Relevant excipient information is shown in Table 11.

[0339] [Table 11]

[0340] Experimental methods and steps: Mouse colon cancer cells CT26 (originating from Nanjing Kebai Biotechnology Co., Ltd., product number: CBP60043) were maintained and passaged by Yingshi Biotechnology (Nanjing) Co., Ltd. Cells were cultured in vitro in monolayers in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Cells were passaged two to three times a week using pancreatin-EDTA digestion. When cells reached exponential growth phase and 80%-90% saturation, they were harvested, counted, and then inoculated.

[0341] 3×10 5 A 0.1 mL cell suspension containing 100 cells was subcutaneously inoculated into the right hindquarters of each mouse. The tumor volume was approximately 57 mm. 3 On day 13 after cell inoculation, the patients were randomly divided into groups based on tumor volume and administered the drugs. The group information is shown in Table 12.

[0342] [Table 12] Note: 1. N: number of mice in each group; 2. Dosage volume: 10 mL / kg based on mouse body weight. When the body weight loss exceeds 15%, the administration to the animals will be stopped, and when the body weight returns to the initial value, the administration will be resumed.

[0343] Preparation information for the test substances and control solvents is shown in Table 13.

[0344] [Table 13]

[0345] Routine observation of laboratory animals: Animal health and mortality were monitored daily, and routine examinations included observing tumor growth and the effects of drug treatment on the animals' daily behavior, such as behavior, food and water intake (visual observation only), weight change, external signs, or other abnormalities. The number of animal deaths and side effects within groups were recorded based on the number of animals in each group.

[0346] Testing Cessation: The animal's health condition continues to deteriorate or the tumor volume exceeds 3000mm 3 If the weight of the animal exceeds 1000 kg / m² or if it is in severe pain or disease, it should be euthanized. If the animal is found to be emaciated, the veterinarian should be notified and it should be euthanized if the animal is: obviously thin, with a weight loss of more than 20%, unable to freely access food and water, or the average tumor volume of the control group is 3000 mm² or more. 3 The animals showed clinical signs of ruffled fur, hunched posture, pale ears, nose, eyes or paws, shortness of breath, convulsions, persistent diarrhea, dehydration, slowness and vocalization, and continued deterioration.

[0347] Tumor Measurements and Laboratory Parameters: The experimental endpoints were to determine whether tumor growth was inhibited, delayed, or cured. Tumor diameters were measured with calipers 2-3 times a week. The formula for calculating tumor volume was V = 0.5 × a × b. 2 where a and b represent the long and short diameters of the tumor, respectively.

[0348] The tumor growth effect of the compound was evaluated by TGI (%), which reflects the tumor growth inhibition rate. The tumor growth inhibition rate TGI (%) was calculated based on the tumor volume on the first day after grouping according to the following formula: TGI (%) = [1 - (mean tumor volume of a certain treatment group - mean tumor volume of the treatment group at the start of treatment) / (mean tumor volume of the solvent control group - mean tumor volume of the solvent control group at the start of treatment)] × 100%.

[0349] Statistical analysis: Statistical analysis was performed using Prism Graphpad software based on tumor volume at the end of the study. Comparisons between multiple groups were analyzed using two-way ANOVA and Fisher's LSD test. Differences were considered significant when p<0.05.

[0350] Test Results: In vivo efficacy study of combined treatment with test substances MRTX1133 and IN10018 in a CT-26 BALB / c mouse subcutaneous allograft tumor model of mouse colon cancer After inoculation of the cells, tumor growth was observed daily. On the 13th day after inoculation, the mice were divided into groups based on tumor volume. The average tumor volume of the assigned group was approximately 57 mm. 3 Due to the tumor burden, the control group was euthanized on the 27th day after inoculation, i.e., the 14th day after group administration, and the remaining treatment groups were euthanized on the 29th day after inoculation, i.e., the 16th day after group administration, at which point all experiments were completed.

[0351] On the 14th day after group administration, the tumor volume in the control group was 2799.4±687.0 mm 3 The tumor volume in the MRTX1133 (5 mg / kg) single agent group was 1067.8 ± 302.1 mm 3 The tumor volume in the MRTX1133 + IN10018 (5 + 25 mg / kg) combination group was 674.9 ± 189.0 mm 3 The tumor volumes on day 14 were combined and compared with the control group. The tumor inhibition rate TGI for the MRTX1133 (5 mg / kg) single-agent group was 63.2% (p<0.0001), while the tumor inhibition rate TGI for the MRTX1133 + IN10018 (5 + 25 mg / kg) dual-drug combination group was 77.5% (p<0.0001), both of which showed significant statistical differences (see Figure 14).

[0352] On the 14th day after group administration, the tumors were too large, so the control group was euthanized. Administration continued until the 16th day, and the remaining treatment groups were observed. The tumor volume in the MRTX1133 (5 mg / kg) single agent group was 1672.1 ± 548.1 mm 3 The tumor volume in the MRTX1133 + IN10018 (5 + 25 mg / kg) combination group was 1013.5 ± 351.8 mm 3 When the two groups were statistically compared, the P value was p<0.0001, which means there was a significant statistical difference, see Figure 14.

[0353] See Table 14 for detailed evaluation of the tumor inhibitory effect of each group. Figure 14 shows the tumor volumes for each dose group over different time periods. Integrating the entire administration cycle, the tumor volumes of the MRTX1133 + IN10018 (5 + 25 mg / kg) dual-drug combination treatment group were all smaller than those of the MRTX1133 (5 mg / kg) monotherapy group, with both being statistically significant. This indicates that the combined administration of MRTX1133 + IN10018 (5 + 25 mg / kg) had a greater tumor growth inhibitory effect, and that IN10018 (25 mg / kg) could significantly improve the therapeutic effect of the combined MRTX1133 + IN10018 (5 + 25 mg / kg) treatment.

[0354] [Table 14] Evaluation of the tumor-inhibitory effect of the test substance on a BALB / c mouse tumor model in which mouse colon cancer CT26 cells were transplanted (based on data from 14 / 16 days after administration in groups) Note: 1. Calculations were based on the number of days after group administration, and the data are mean ± standard error (mean ± SD). 2. TGI(%)=[1-(T 14 -T0) / (V 14 -V0)] × 100% 3, ****: p<0.0001, vs. control group, Two-way ANOVA, 4, ****:p<0.0001, vs. MRTX1133+IN10018(5+25mg / kg) group, Two-way ANOVA.

[0355] In vivo efficacy study of the combined treatment of test substances MRTX1133, TIGIT, and IN10018 in a CT26 mouse colon cancer subcutaneous allograft tumor model in BALB / c mice After inoculation of the cells, tumor growth was observed daily. As described above, on day 13 after inoculation, the mice were divided into groups based on tumor volume. The average tumor volume of the assigned group was approximately 57 mm. 3Due to the tumor burden, the control group was euthanized on the 27th day after inoculation, i.e., the 14th day after group administration, and the remaining treatment groups were euthanized on the 29th day after inoculation, i.e., the 16th day after group administration, at which point all experiments were completed.

[0356] On the 14th day after group administration, the tumor volume in the control group was 2799.4±687.0 mm 3 The tumor volumes in the MRTX1133 (5 mg / kg) and TIGIT (3 mg / kg) single-agent groups were 1067.8 ± 302.1 mm, respectively. 3 and 976.8±640.4mm 3 The tumor volumes in the MRTX1133 + IN10018 (5 + 25 mg / kg) dual-drug combination group and the IN10018 + TIGIT (25 + 3 mg / kg) dual-drug combination group were 674.9 ± 189.0 mm 3 and 1315.6±870.2 mm 3 The tumor volume in the MRTX1133 + IN10018 + TIGIT (5 + 25 + 3 mg / kg) triple combination group was 535.5 ± 288.9 mm 3 When comparing the combined tumor volumes with the control group, the tumor inhibition rates (TGI) for the MRTX1133 (5 mg / kg) monotherapy group and the TIGIT (3 mg / kg) monotherapy group were 63.2% (p<0.0001) and 66.5% (p<0.0001), respectively. The tumor inhibition rates (TGI) for the MRTX1133 + IN10018 (5 + 25 mg / kg) dual-drug combination group and the IN10018 + TIGIT (25 + 3 mg / kg) dual-drug combination group were 77.5% (p<0.0001) and 54.1% (p<0.0001), respectively. The tumor inhibition rate (TGI) for the MRTX1133 + IN10018 + TIGIT (5 + 25 + 3 mg / kg) triple-drug combination group was 82.5% (p<0.0001), all of which showed significant differences.

[0357] On the 14th day after group administration, the tumors were too large, so the control group was euthanized. Administration continued until the 16th day, and the remaining treatment groups were observed. The tumor volumes of the MRTX1133 (5 mg / kg) single agent group and the TIGIT (3 mg / kg) single agent group were 1672.1 ± 548.1 mm, respectively. 3 and 1225.8±814.5mm3 The tumor volumes in the MRTX1133 + IN10018 (5 + 25 mg / kg) dual-drug combination group and the IN10018 + TIGIT (25 + 3 mg / kg) dual-drug combination group were 1013.5 ± 351.8 mm 3 and 1857±1240.4mm 3 The tumor volume in the MRTX1133 + IN10018 + TIGIT (5 + 25 + 3 mg / kg) triple combination group was 809.3 ± 511.4 mm 3 Statistical analysis was performed on the combined tumor volumes compared with the MRTX1133 + IN10018 + TIGIT (5 + 25 + 3 mg / kg) triple combination group. The P values ​​for the MRTX1133 (5 mg / kg) single-agent group and the TIGIT (3 mg / kg) single-agent group were p<0.0001 and p=0.0339, respectively. The P values ​​for the MRTX1133 + IN10018 (5 + 25 mg / kg) double-agent group and the IN10018 + TIGIT (25 + 3 mg / kg) double-agent group were p=0.2965 and p<0.0001, respectively. All of these were statistically significant compared with the combination treatment groups other than MRTX1133 + IN10018 (5 + 25 mg / kg).

[0358] For detailed evaluation of the tumor inhibition effect of each group, see Table 15. The tumor volumes of each dose group over different time ranges are shown in Figure 15. Combining the entire administration cycle, the MRTX1133 + IN10018 + TIGIT (5 + 25 + 3 mg / kg) triple combination treatment group had one of the smallest tumor volumes.

[0359] [Table 15] Evaluation of the tumor-inhibitory effect of the test substance on a BALB / c mouse tumor model in which mouse colon cancer CT26 cells were transplanted (based on data from 14 / 16 days after administration in groups) Note: 1. Calculations were based on the number of days after group administration, and the data are mean ± standard error (mean ± SD). 2. TGI(%)=[1-(T 14 -T0) / (V 14 -V0)] × 100% 3, ****: p<0.0001, vs. control group, Two-way ANOVA, 4, *:p<0.05, ****:p<0.0001, vs. MRTX1133+IN10018+TIGIT(5+25+3mg / kg) group, Two-way ANOVA.

[0360] A study of changes in body weight and clinical status in a BALB / c mouse subcutaneous allograft tumor model of CT26 mouse colon cancer during combined treatment with the test substances MRTX1133, TIGIT, and IN10018 The experiment was carried out according to the administration scheme. During the experiment, the animals' activities such as food and water intake were observed daily, and their body weights were recorded 2-3 times a week. On the day the animals in each group were euthanized, i.e., on the 14th day after group administration for the control group and on the 16th day after group administration for the remaining treatment groups, the body weight of the control group increased from 19.4 g on the day of group administration (Day 0) to 23.7 g on Day 14, a weight change rate of 22.0%. The mean body weights of the MRTX1133 (5 mg / kg) single agent group and the TIGIT (3 mg / kg) single agent group increased from 19.4 g and 19.6 g on the day of group administration (Day 0) to 22.3 g and 23.1 g on Day 16, respectively, a weight change rate of 15.1% and 18.2%, respectively. The body weights of the MRTX1133 + IN10018 (5 + 25 mg / kg) dual drug combination group and the IN10018 + TIGIT (25 + 3 mg / kg) dual drug combination group increased from 19.4 g and 19.6 g on Day 0 to 22.3 g and 23.1 g on Day 16, respectively, a weight change rate of 15.1% and 18.2%, respectively. The weight of the MRTX1133+IN10018+TIGIT (5+25+3mg / kg) triple-drug combination group increased from 19.4g and 19.0g on Day 0 to 21.4g and 22.8g on Day 16, respectively, representing a weight change rate of 10.7% and 19.6%, respectively. The weight of the MRTX1133+IN10018+TIGIT (5+25+3mg / kg) triple-drug combination group increased from 19.5g on Day 0 to 21.2g on Day 16, representing a weight change rate of 8.5%.

[0361] Overall, the animals in each group showed no obvious weight loss, were in good mental condition, and had normal food intake throughout the entire administration cycle. The weight data for each group are shown in Table 16, and the weight changes and rate of change over different time periods for each dose group are shown in Figure 16. The animals in each group showed no obvious weight loss, were in good mental condition, had normal food intake, and showed tolerance to the combined treatment of MRTX1133 (5 mg / kg), TIGIT (3 mg / kg), and IN10018 (25 mg / kg).

[0362] [Table 16] Evaluation of body weight changes in a BALB / c mouse model transplanted with mouse colon cancer CT26 cells (based on data from 14 / 16 days after administration in groups) Note: 1. Based on the number of days after group administration, the number of surviving animals on day 0 was divided by the number of surviving animals on day 14 (control group) or day 16 (remaining treatment groups). 2. Data are mean ± standard error (mean ± SD). 3. For the control group, data from the 14th day after group administration was used, and for the remaining treatment groups, data from the 16th day after group administration was used for calculations. 4. Weight change rate = [1-(W 14 / 16 -W0) / W0]*100%

[0363] Example 10: Study of target induction of immunogenic cell death of mouse breast cancer 4T1 cells in vitro by test compounds Lurbinectedin and AMP945 Test materials: 1) Drugs used in this experiment Lurbinectedin was provided by DC Chemicals, Lot No: DC12502 AMP945 is provided by MCE, Lot No: 143253 2) Antibodies used in this experiment Recombinant Alexa Fluor® 647 Fluorescent Anti-Calreticulin Antibody (Abcam, Cat No: ab196159, Lot No: CR33676773). Annexin V-Apoptosis Detection Kit (Beyotime, Cat No: C1062L, Lot No: 122221220706).

[0364] Experimental Method: 4T1 cells (originating from Nanjing Kebai Biotechnology Co., Ltd., product number: CBP60352) were cultured in RPMI 1640 (Shanghai Yuanpei, Cat No.: L210KJ, Lot No.: F210916) + 10% FBS (Gibco, Cat No.: 10099-141c, Lot No.: 2158737cp) at 37°C and 5% CO2. They were passaged two to three times a week by routine trypsin digestion. When cells reached exponential growth phase and 80% to 90% confluence, they were harvested and plated. 4T1 cells were digested with trypsin, harvested, and counted. Based on the counting results, the cells were diluted with RPMI 1640 + 10% FBS to a concentration of 50,000 cells per milliliter and then plated into a 12-well cell culture plate, with 2 ml of cell suspension (100,000 cells) plated into each well. After plating, the cells were cultured in a 37°C, 5% CO2 incubator. After 24 hours of incubation, the cells were divided into six groups: Group 1 (control) with medium; Group 2 (AMP945 at 3 μM); Group 3 (AMP945 at 6 μM); Group 4 (lurbinectedin at 0.002 μM); Group 5 (AMP945 (3 μM) + lurbinectedin (0.002 μM); and Group 6 (AMP945 (6 μM) + lurbinectedin (0.002 μM). The drugs were mixed and cultured at 37°C in a 5% CO2 incubator for 48 hours.

[0365] Experimental results After 48 hours of drug treatment, cells were harvested and subjected to flow analysis. Cells were washed twice with flow cytometry buffer (PBS + 2% FBS), and 0.5 μl of AF647 anti-calreticulin antibody (Abcam) was added to each well and mixed. After incubation at 4°C under light-protected conditions, flow cytometry buffer was added. Using an annexin staining kit (Beyotime), 195 μl of Annexin-V-FITC conjugate was added and mixed by spraying onto the cells. 5 μl of Annexin-V-FITC antibody was added and mixed gently. Finally, 10 μl of PI dye was added and mixed. After incubation at room temperature under light-protected conditions for 15 minutes, the samples were transferred to a flow cytometer for signal detection.

[0366] The flow cytometer analysis results showed that the CRT positive rate and Annexin-V positive rate in the dual drug combination group were significantly higher than those in the single drug group and the control group (see FIG. 17).

[0367] Example 11: Study of target induction of immunogenic cell death of mouse breast cancer 4T1 cells in vitro by test compounds Crizotinib and AMP945 Test materials: 1) Drugs used in this experiment Crizotinib was provided by MCE, Lot No: 06049 AMP945 is provided by MCE, Lot No: 143253 2) Antibodies used in this experiment Recombinant Alexa Fluor® 647 Fluorescent Anti-Calreticulin Antibody (Abcam, Cat No: ab196159, Lot No: CR33676773). Annexin V-Apoptosis Detection Kit (Beyotime, Cat No: C1062L, Lot No: 122221220706).

[0368] Experimental Method: 4T1 cells (originating from Nanjing Kebai Biotechnology Co., Ltd., product number: CBP60352) were cultured in RPMI 1640 (Shanghai Yuanpei, Cat No.: L210KJ, Lot No.: F210916) + 10% FBS (Gibco, Cat No.: 10099-141c, Lot No.: 2158737cp) at 37°C and 5% CO2. They were passaged two to three times a week by routine trypsin digestion. When cells reached exponential growth phase and 80% to 90% confluence, they were harvested and plated. 4T1 cells were digested with trypsin, harvested, and counted. Based on the counting results, the cells were diluted with RPMI 1640 + 10% FBS to a concentration of 50,000 cells per milliliter and then plated into 12-well cell culture plates. 2 ml of cell suspension (100,000 cells) was plated per well. After plating, the cells were cultured in a 37°C, 5% CO2 incubator. After 24 hours of cell proliferation, six groups were established: Group 1 (control) with medium; Group 2 (AMP945 at 3 μM; Group 3 (AMP945 at 6 μM; Group 4 (crizotinib at 3 μM; Group 5 (AMP945 (3 μM) combined with crizotinib (3 μM); Group 6 (AMP945 (6 μM) combined with crizotinib (3 μM)). The drugs were mixed and cultured at 37°C in a 5% CO2 incubator for 48 hours.

[0369] Experimental results After 48 hours of drug treatment, cells were harvested and subjected to flow analysis. Cells were washed twice with flow cytometry buffer (PBS + 2% FBS), and 0.5 μl of AF647 anti-calreticulin antibody (Abcam) was added to each well and mixed. After incubation at 4°C under light-protected conditions, flow cytometry buffer was added. Using an annexin staining kit (Beyotime), 195 μl of Annexin-V-FITC binding buffer was added and mixed by spraying onto the cells. 5 μl of Annexin-V-FITC antibody was added and mixed gently. Finally, 10 μl of PI dye was added and mixed. After incubation at room temperature under light-protected conditions for 15 minutes, the samples were transferred to a flow cytometer for signal detection.

[0370] The flow cytometer analysis results showed that the CRT positive rate and Annexin-V positive rate in the dual drug combination group were significantly higher than those in the single drug group and the control group (see FIG. 18).

[0371] All references mentioned in this application are incorporated herein by reference in their entirety as if each reference were individually cited. After reading the present disclosure, one skilled in the art will understand that various changes or modifications can be made to the present invention, and that equivalents thereof are also included in the scope defined by the appended claims of this application.

Claims

1. Use of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

2. A pharmaceutical combination product of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor for treating a tumor in a subject, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

3. A method for treating a tumor, comprising administering to a subject therapeutically effective amounts of a FAK inhibitor, an immunogenic cell death inducer, and an immune checkpoint inhibitor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

4. 4. The use, pharmaceutical combination product or method according to any one of claims 1 to 3, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945 or a pharmaceutically acceptable salt thereof, more preferably IN10018 or a pharmaceutically acceptable salt thereof, in particular IN10018 tartrate, and the structure of IN10018 is as follows: 【Chemical 1】

5. The use, pharmaceutical combination product or method according to any one of claims 1 to 4, wherein said immunogenic cell death inducer is an inhibitor of RNA polymerase II.

6. 6. The use, pharmaceutical combination product or method of claim 5, wherein said inhibitor of RNA polymerase II is lurbinectedin, SEL-120 or a pharmaceutically acceptable salt thereof.

7. 7. The use, pharmaceutical combination product or method of claim 5 or 6, wherein said inhibitor of RNA polymerase II is lurbinectedin.

8. The use, pharmaceutical combination product or method according to any one of claims 1 to 4, wherein said immunogenic cell death inducer is an ALK / ROS1 inhibitor.

9. The ALK / ROS1 inhibitors include crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG- 2449, Brigatinib, TQ-B3101, Entrectinib, Repotrectinib or a pharmaceutically acceptable salt thereof, in particular Crizotinib, Entrectinib or a pharmaceutically acceptable salt thereof. The use, pharmaceutical combination product or method according to claim 8.

10. 10. The use, pharmaceutical combination product or method of claim 8 or 9, wherein said ALK / ROS1 inhibitor is crizotinib.

11. The use, pharmaceutical combination product or method according to any one of claims 1 to 4, wherein said immunogenic cell death inducer is a KRAS G12C inhibitor.

12. 12. The use, pharmaceutical combination product or method according to claim 11, wherein said KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, Sotorasib (Sotorasib / AMG510), Adagrasib (MRTX849), GDC-6036 or a pharmaceutically acceptable salt thereof, in particular D-1553, Sotorasib (Sotorasib / AMG510) or a pharmaceutically acceptable salt thereof.

13. The use, pharmaceutical combination product or method according to claim 11 or 12, wherein said KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

14. The use, pharmaceutical combination product or method according to any one of claims 1 to 4, wherein said immunogenic cell death inducer is a KRAS G12D inhibitor.

15. 15. The use, pharmaceutical combination product or method of claim 14, wherein said KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000 or a pharmaceutically acceptable salt thereof.

16. 16. The use, pharmaceutical combination product or method of claim 14 or 15, wherein said KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

17. The use, pharmaceutical combination product or method according to any one of claims 1 to 16, wherein said immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor or a TIGIT antibody.

18. The immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and further, the anti-PD-1 / PD-L1 antibody is selected from the group consisting of pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, and avelumab. , Atezolizumab, Camrelizumab, Sintilimab, Cemiplimab, Envafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.

19. 18. The use, pharmaceutical combination product or method of any one of claims 1 to 17, wherein said immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and further wherein said PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.

20. The immune checkpoint inhibitor is a TIGIT antibody, and the TIGIT antibody is selected from the group consisting of osipelimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, belrestotug, etigilimab, ONO-4686, JS 18. The use, pharmaceutical combination product or method of any one of claims 1 to 17, wherein the active ingredient is Benzyl Alcohol-Inhibitor, ...

21. 5. The use, pharmaceutical combination product or method according to any one of claims 1 to 4, wherein said FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, said immunogenic cell death inducer is lurbinectedin, and said immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

22. 5. The use, pharmaceutical combination product or method according to any one of claims 1 to 4, wherein said FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, said immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and said immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

23. 5. The use, pharmaceutical combination product or method according to any one of claims 1 to 4, wherein said FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, said immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and said immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

24. 5. The use, pharmaceutical combination product or method according to any one of claims 1 to 4, wherein said FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, said immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and said immune checkpoint inhibitor is a TIGIT antibody.

25. The use, pharmaceutical combination product or method according to any one of claims 1 to 24, wherein said FAK inhibitor, said immunogenic cell death inducer and said immune checkpoint inhibitor are administered to said subject simultaneously or sequentially.

26. The tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine tumor, ovarian cancer, salivary gland cancer, metastatic tumors from spindle cell carcinoma, anaplastic large cell lymphoma, thyroid cancer, thyroid cancer, ovarian cancer, salivary gland cancer, thyroid ...

26. The use, pharmaceutical combination product or method according to any one of claims 1 to 25, wherein the cancer is undifferentiated carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematopoietic malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), gastric cancer, malignant melanoma or pancreatic cancer.

27. 27. The use, pharmaceutical combination product or method according to any one of claims 1 to 26, wherein said tumor is lung cancer, colon cancer (including large bowel cancer) or breast cancer.

28. (a) a FAK inhibitor; and (b) an immunogenic cell death inducer; and (c) an immune checkpoint inhibitor, The kit or pharmaceutically acceptable composition, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

29. The kit or composition according to claim 28, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof, more preferably IN10018 or a pharmaceutically acceptable salt thereof, particularly IN10018 tartrate, and the structure of IN10018 is as follows: 【Chemistry 2】

30. 30. The kit or composition of claim 28 or 29, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II.

31. The kit or composition of claim 30, wherein the inhibitor of RNA polymerase II is lurbinectedin, SEL-120, or a pharmaceutically acceptable salt thereof.

32. 32. The kit or composition of claim 30 or 31, wherein the inhibitor of RNA polymerase II is lurbinectedin.

33. 30. The kit or composition of claim 28 or 29, wherein the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

34. The ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib, or a pharmaceutically acceptable salt thereof, in particular, crizotinib, entrectinib, or a pharmaceutically acceptable salt thereof. The kit or composition of claim 33.

35. 35. The kit or composition of claim 33 or 34, wherein the ALK / ROS1 inhibitor is crizotinib or a pharmaceutically acceptable salt thereof.

36. 30. The kit or composition of claim 28 or 29, wherein the immunogenic cell death inducer is a KRAS G12C inhibitor.

37. The kit or composition according to claim 36, wherein the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, sotorasib (sotorasib / AMG510), adagrasib (MRTX849), GDC-6036, or a pharmaceutically acceptable salt thereof, in particular D-1553, sotorasib (sotorasib / AMG510), or a pharmaceutically acceptable salt thereof.

38. The kit or composition according to claim 36 or 37, wherein the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

39. 30. The kit or composition of claim 28 or 29, wherein the immunogenic cell death inducer is a KRAS G12D inhibitor.

40. 40. The kit or composition of claim 39, wherein the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000, or a pharmaceutically acceptable salt thereof.

41. 41. The kit or composition of claim 39 or 40, wherein the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

42. The kit or composition according to any one of claims 28 to 41, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

43. The immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and the anti-PD-1 / PD-L1 antibody is selected from the group consisting of pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, and avelumab.

43. The kit or composition according to any one of claims 28 to 42, wherein the antibody is selected from the group consisting of atezolizumab, camrelizumab, sintilimab, cemiplimab, envafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, and MX-10181.

44. The kit or composition of any one of claims 28 to 42, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and further wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001.

45. The immune checkpoint inhibitor is a TIGIT antibody, and the TIGIT antibody is selected from the group consisting of osipelimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, belrestotug, etigilimab, and ONO-468. 6, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321.

46. 30. The kit or composition of claim 28 or 29, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is lurbinectedin, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

47. The kit or composition according to claim 28 or 29, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is crizotinib or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

48. The kit or composition according to claim 28 or 29, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is D-1553 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, in particular an anti-PD-1 / PD-L1 antibody.

49. 30. The kit or composition of claim 28 or 29, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the immunogenic cell death inducer is MRTX1133 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is a TIGIT antibody.

50. The kit or composition according to any one of claims 28 to 49, for use as a medicament.

51. The drug is used to treat tumors, and the tumors include metastases from bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine tumor, ovarian cancer, salivary gland cancer, and spindle cell carcinoma.

51. The kit or composition of claim 50, wherein the cancer is selected from the group consisting of thyroid cancer, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, and hematopoietic malignancies, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML), and preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), gastric cancer, malignant melanoma, and pancreatic cancer.

52. 52. The kit or composition of claim 51, wherein the tumor is lung cancer, colon cancer (including large bowel cancer), or breast cancer.

53. A FAK inhibitor for enhancing immunogenic cell death induced by an immunogenic cell death inducer in the treatment of a tumor, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II, an ALK / ROS1 inhibitor, a KRAS G12C inhibitor, or a KRAS G12D inhibitor.

54. The FAK inhibitor according to claim 53, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof, more preferably IN10018 or a pharmaceutically acceptable salt thereof, particularly IN10018 tartrate, and the structure of IN10018 is as follows: 【Chemistry 3】

55. 55. The FAK inhibitor of claim 53 or 54, wherein the immunogenic cell death inducer is an inhibitor of RNA polymerase II.

56. The FAK inhibitor according to claim 55, wherein the inhibitor of RNA polymerase II is lurbinectedin, SEL-120 or a pharmaceutically acceptable salt thereof, in particular lurbinectedin.

57. 55. The FAK inhibitor of claim 53 or 54, wherein the immunogenic cell death inducer is an ALK / ROS1 inhibitor.

58. The ALK / ROS1 inhibitor is crizotinib, SIM-0201, XZP-3621, TQ-B3139, SAF-189s, ceritinib, lorlatinib (PF-06463922, lorlatinib), alectinib, ensartinib, APG-2449, brigatinib, TQ-B3101, entrectinib, repotrectinib, or a pharmaceutically acceptable salt thereof, in particular, crizotinib, entrectinib, or a pharmaceutically acceptable salt thereof. The FAK inhibitor according to claim 57.

59. The FAK inhibitor of claim 57 or 58, wherein the ALK / ROS1 inhibitor is crizotinib.

60. 55. The FAK inhibitor of claim 53 or 54, wherein the immunogenic cell death inducer is a KRAS G12C inhibitor.

61. The FAK inhibitor according to claim 60, wherein the KRAS G12C inhibitor is D-1553, ARS-3248, GF-105, JAB-21822, JDQ-443, LY-3537982, Sotorasib (sotorasib / AMG510), Adagrasib (MRTX849), GDC-6036, or a pharmaceutically acceptable salt thereof, in particular D-1553, Sotorasib (sotorasib / AMG510), or a pharmaceutically acceptable salt thereof.

62. The FAK inhibitor according to claim 60 or 61, wherein the KRAS G12C inhibitor is D-1553 or a pharmaceutically acceptable salt thereof.

63. 55. The FAK inhibitor of claim 53 or 54, wherein the immunogenic cell death inducer is a KRAS G12D inhibitor.

64. The FAK inhibitor of claim 63, wherein the KRAS G12D inhibitor is MRTX1133, HRS-4642, JAB-22000, or a pharmaceutically acceptable salt thereof.

65. 65. The FAK inhibitor of claim 63 or 64, wherein the KRAS G12D inhibitor is MRTX1133 or a pharmaceutically acceptable salt thereof.

66. The drug is used to treat tumors, and the tumors include metastatic tumors from bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), malignant melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine tumor, ovarian cancer, salivary gland cancer, spindle cell carcinoma, The FAK inhibitor according to any one of claims 53 to 65, which is anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematopoietic malignant tumor, for example, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), gastric cancer, malignant melanoma, or pancreatic cancer.

67. 67. The FAK inhibitor of claim 66, wherein the tumor is lung cancer, colon cancer (including colorectal cancer), or breast cancer.

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