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靶向KRAS G12突变肿瘤药物的作用机制及研究进展
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Abstract:
Kirsten大鼠肉瘤病毒癌基因同源物(KRAS)是人类癌症中常见的突变癌基因，KRAS G12突变是KRAS最常见的突变类型。突变导致KRAS蛋白在细胞信号转导中持续活化，促进肿瘤的生长与转移。尽管KRAS在过去被视作不可成药的靶点，但近年来已有多款KRAS G12C靶向药物上市或进入临床研究阶段。本文对各类KRAS G12抑制剂的代表化合物、作用机制及生物活性的研究进展进行综述，旨在为KRAS G12小分子抑制剂抗肿瘤药物的开发提供思路和参考。
The Kirsten rat sarcoma viral oncogene homolog (KRAS) is a frequently mutated oncogene in human cancers, with the KRAS G12 mutation being the most common type of KRAS mutation. This mutation leads to the continuous activation of the KRAS protein in cellular signal transduction, promoting tumor growth and metastasis. Although KRAS was historically considered an undruggable target, several KRAS G12C-targeted drugs have been approved or entered clinical research stages in recent years. This article reviews the representative compounds, mechanisms of action, and research progress on the biological activities of various KRAS G12 inhibitors, aiming to provide insights and references for the development of small-molecule inhibitors targeting KRAS G12 in anti-tumor drug discovery.
| [1] | Uprety, D. and Adjei, A.A. (2020) KRAS: From Undruggable to a Druggable Cancer Target. Cancer Treatment Reviews, 89, Article ID: 102070. https://doi.org/10.1016/j.ctrv.2020.102070 |
| [2] | Liu, P., Wang, Y. and Li, X. (2019) Targeting the Untargetable KRAS in Cancer Therapy. Acta Pharmaceutica Sinica B, 9, 871-879. https://doi.org/10.1016/j.apsb.2019.03.002 |
| [3] | Parikh, K., Banna, G., Liu, S.V., Friedlaender, A., Desai, A., Subbiah, V., et al. (2022) Drugging KRAS: Current Perspectives and State-of-Art Review. Journal of Hematology & Oncology, 15, Article No. 152. https://doi.org/10.1186/s13045-022-01375-4 |
| [4] | Meng, M., Zhong, K., Jiang, T., Liu, Z., Kwan, H.Y. and Su, T. (2021) The Current Understanding on the Impact of KRAS on Colorectal Cancer. Biomedicine & Pharmacotherapy, 140, Article ID: 111717. https://doi.org/10.1016/j.biopha.2021.111717 |
| [5] | Luo, J. (2021) KRAS Mutation in Pancreatic Cancer. Seminars in Oncology, 48, 10-18. https://doi.org/10.1053/j.seminoncol.2021.02.003 |
| [6] | Huang, L., Guo, Z., Wang, F. and Fu, L. (2021) KRAS Mutation: From Undruggable to Druggable in Cancer. Signal Transduction and Targeted Therapy, 6, Article No. 386. https://doi.org/10.1038/s41392-021-00780-4 |
| [7] | Stephen, A.G., Esposito, D., Bagni, R.K. and McCormick, F. (2014) Dragging Ras Back in the Ring. Cancer Cell, 25, 272-281. https://doi.org/10.1016/j.ccr.2014.02.017 |
| [8] | Pantsar, T. (2020) The Current Understanding of KRAS Protein Structure and Dynamics. Computational and Structural Biotechnology Journal, 18, 189-198. https://doi.org/10.1016/j.csbj.2019.12.004 |
| [9] | Hall, B.E., Bar-Sagi, D. and Nassar, N. (2002) The Structural Basis for the Transition from Ras-GTP to Ras-GDP. Proceedings of the National Academy of Sciences, 99, 12138-12142. https://doi.org/10.1073/pnas.192453199 |
| [10] | Iversen, L., Tu, H., Lin, W., Christensen, S.M., Abel, S.M., Iwig, J., et al. (2014) Ras Activation by SOS: Allosteric Regulation by Altered Fluctuation Dynamics. Science, 345, 50-54. https://doi.org/10.1126/science.1250373 |
| [11] | Bos, J.L., Rehmann, H. and Wittinghofer, A. (2007) GEFs and GAPs: Critical Elements in the Control of Small G Proteins. Cell, 129, 865-877. https://doi.org/10.1016/j.cell.2007.05.018 |
| [12] | Moore, A.R., Rosenberg, S.C., McCormick, F. and Malek, S. (2020) RAS-Targeted Therapies: Is the Undruggable Drugged? Nature Reviews Drug Discovery, 19, 533-552. https://doi.org/10.1038/s41573-020-0068-6 |
| [13] | Indini, A., Rijavec, E., Ghidini, M., Cortellini, A. and Grossi, F. (2021) Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors. Pharmaceutics, 13, Article 653. https://doi.org/10.3390/pharmaceutics13050653 |
| [14] | Judd, J., Abdel Karim, N., Khan, H., Naqash, A.R., Baca, Y., Xiu, J., et al. (2021) Characterization of KRAS Mutation Subtypes in Non-Small Cell Lung Cancer. Molecular Cancer Therapeutics, 20, 2577-2584. https://doi.org/10.1158/1535-7163.mct-21-0201 |
| [15] | Waters, A.M. and Der, C.J. (2018) KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harbor Perspectives in Medicine, 8, a031435. https://doi.org/10.1101/cshperspect.a031435 |
| [16] | Simanshu, D.K., Nissley, D.V. and McCormick, F. (2017) RAS Proteins and Their Regulators in Human Disease. Cell, 170, 17-33. https://doi.org/10.1016/j.cell.2017.06.009 |
| [17] | Sebastian, M., Eberhardt, W.E.E., Hoffknecht, P., Metzenmacher, M., Wehler, T., Kokowski, K., et al. (2021) KRAS G12C-Mutated Advanced Non-Small Cell Lung Cancer: A Real-World Cohort from the German Prospective, Observational, Nation-Wide CRISP Registry (AIO-TRK-0315). Lung Cancer, 154, 51-61. https://doi.org/10.1016/j.lungcan.2021.02.005 |
| [18] | Gao, G., Liao, W., Ma, Q., Zhang, B., Chen, Y. and Wang, Y. (2020) KRAS G12D Mutation Predicts Lower TMB and Drives Immune Suppression in Lung Adenocarcinoma. Lung Cancer, 149, 41-45. https://doi.org/10.1016/j.lungcan.2020.09.004 |
| [19] | Zdanov, S., Mandapathil, M., Abu Eid, R., Adamson-Fadeyi, S., Wilson, W., Qian, J., et al. (2016) Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells. Cancer Immunology Research, 4, 354-365. https://doi.org/10.1158/2326-6066.cir-15-0241 |
| [20] | Adachi, Y., Ito, K., Hayashi, Y., Kimura, R., Tan, T.Z., Yamaguchi, R., et al. (2020) Epithelial-to-Mesenchymal Transition Is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C-Mutant Non-Small Cell Lung Cancer. Clinical Cancer Research, 26, 5962-5973. https://doi.org/10.1158/1078-0432.ccr-20-2077 |
| [21] | Canon, J., Rex, K., Saiki, A.Y., Mohr, C., Cooke, K., Bagal, D., et al. (2019) The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity. Nature, 575, 217-223. https://doi.org/10.1038/s41586-019-1694-1 |
| [22] | Ostrem, J.M., Peters, U., Sos, M.L., Wells, J.A. and Shokat, K.M. (2013) K-Ras (G12C) Inhibitors Allosterically Control GTP Affinity and Effector Interactions. Nature, 503, 548-551. https://doi.org/10.1038/nature12796 |
| [23] | Blair, H.A. (2021) Sotorasib: First Approval. Drugs, 81, 1573-1579. https://doi.org/10.1007/s40265-021-01574-2 |
| [24] | Fell, J.B., Fischer, J.P., Baer, B.R., Blake, J.F., Bouhana, K., Briere, D.M., et al. (2020) Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer. Journal of Medicinal Chemistry, 63, 6679-6693. https://doi.org/10.1021/acs.jmedchem.9b02052 |
| [25] | Dhillon, S. (2023) Adagrasib: First Approval. Drugs, 83, 275-285. https://doi.org/10.1007/s40265-023-01839-y |
| [26] | Yaeger, R., Uboha, N.V., Pelster, M.S., Bekaii-Saab, T.S., Barve, M., Saltzman, J., et al. (2024) Efficacy and Safety of Adagrasib Plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer. Cancer Discovery, 14, 982-993. https://doi.org/10.1158/2159-8290.cd-24-0217 |
| [27] | Briere, D.M., Li, S., Calinisan, A., Sudhakar, N., Aranda, R., Hargis, L., et al. (2021) The KRASG12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy. Molecular Cancer Therapeutics, 20, 975-985. https://doi.org/10.1158/1535-7163.mct-20-0462 |
| [28] | Jänne, P.A., Smit, E.F., de Marinis, F., Laskin, J., Gomez, M.D., Gadgeel, S., et al. (2022) LBA4 Preliminary Safety and Efficacy of Adagrasib with Pembrolizumab in Treatment-Naïve Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring a KRASG12C Mutation. Immuno-Oncology and Technology, 16, Article ID: 100360. https://doi.org/10.1016/j.iotech.2022.100360 |
| [29] | Mok, T.S.K., Lawler, W.E., Shum, M.K., Dakhil, S.R., Spira, A.I., Barlesi, F., et al. (2021) KRYSTAL-12: A Randomized Phase 3 Study of Adagrasib (MRTX849) versus Docetaxel in Patients (pts) with Previously Treated Non-Small-Cell Lung Cancer (NSCLC) with KRASG12C Mutation. Journal of Clinical Oncology, 39, TPS9129-TPS9129. https://doi.org/10.1200/jco.2021.39.15_suppl.tps9129 |
| [30] | Zhou, Q., Meng, X., Sun, L., Huang, D., Yang, N., Yu, Y., et al. (2024) Efficacy and Safety of KRAS G12C Inhibitor IBI351 Monotherapy in Patients with Advanced NSCLC: Results from a Phase 2 Pivotal Study. Journal of Thoracic Oncology, 19, 1630-1639. https://doi.org/10.1016/j.jtho.2024.08.005 |
| [31] | Shi, Z., Weng, J., Niu, H., Yang, H., Liu, R., Weng, Y., et al. (2023) D‐1553: A Novel KRASG12C Inhibitor with Potent and Selective Cellular and in Vivo Antitumor Activity. Cancer Science, 114, 2951-2960. https://doi.org/10.1111/cas.15829 |
| [32] | Li, Z., Dang, X., Huang, D., Jin, S., Li, W., Shi, J., et al. (2024) Garsorasib in Patients with KRASG12C-Mutated Non-Small-Cell Lung Cancer in China: An Open-Label, Multicentre, Single-Arm, Phase 2 Trial. The Lancet Respiratory Medicine, 12, 589-598. https://doi.org/10.1016/s2213-2600(24)00110-3 |
| [33] | Cassier, P.A., Dooms, C.A., Gazzah, A., Felip, E., Steeghs, N., Rohrberg, K.S., et al. (2023) KontRASt-01 Update: Safety and Efficacy of JDQ443 in KRAS G12C-Mutated Solid Tumors Including Non-Small Cell Lung Cancer (NSCLC). Journal of Clinical Oncology, 41, 9007-9007. https://doi.org/10.1200/jco.2023.41.16_suppl.9007 |
| [34] | Shi, Y., Fang, J., Xing, L., Yao, Y., Zhang, J., Liu, L., et al. (2025) Glecirasib in KRASG12C-Mutated Nonsmall-Cell Lung Cancer: A Phase 2b Trial. Nature Medicine, 31, 894-900. https://doi.org/10.1038/s41591-024-03401-z |
| [35] | Purkey, H. (2022) Abstract ND11: Discovery of GDC-6036, a Clinical Stage Treatment for KRAS G12C-Positive Cancers. Cancer Research, 82, ND11. https://doi.org/10.1158/1538-7445.am2022-nd11 |
| [36] | Peng, S., Si, C., Zhang, Y., Van Horn, R.D., Lin, X., Gong, X., et al. (2021) Abstract 1259: Preclinical Characterization of LY3537982, a Novel, Highly Selective and Potent KRAS-G12C Inhibitor. Cancer Research, 81, Article 1259. https://doi.org/10.1158/1538-7445.am2021-1259 |
| [37] | Murciano-Goroff, Y.R., Heist, R.S., Kuboki, Y., Koyama, T., Ammakkanavar, N.R., Hollebecque, A., et al. (2023) Abstract CT028: A First-in-Human Phase 1 Study of LY3537982, a Highly Selective and Potent KRAS G12C Inhibitor in Patients with KRAS G12C-Mutant Advanced Solid Tumors. Cancer Research, 83, CT028. https://doi.org/10.1158/1538-7445.am2023-ct028 |
| [38] | Yu, Z., He, X., Wang, R., Xu, X., Zhang, Z., Ding, K., et al. (2023) Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles. Journal of the American Chemical Society, 145, 20403-20411. https://doi.org/10.1021/jacs.3c05899 |
| [39] | Wang, X., Allen, S., Blake, J.F., Bowcut, V., Briere, D.M., Calinisan, A., et al. (2021) Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. Journal of Medicinal Chemistry, 65, 3123-3133. |
| [40] | Wei, D., Wang, L., Zuo, X., Maitra, A. and Bresalier, R.S. (2024) A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer. Clinical Cancer Research, 30, 655-662. https://doi.org/10.1158/1078-0432.ccr-23-2098 |
| [41] | Titze-de-Almeida, R., David, C. and Titze-de-Almeida, S.S. (2017) The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. Pharmaceutical Research, 34, 1339-1363. https://doi.org/10.1007/s11095-017-2134-2 |
| [42] | Zorde Khvalevsky, E., Gabai, R., Rachmut, I.H., Horwitz, E., Brunschwig, Z., Orbach, A., et al. (2013) Mutant KRAS Is a Druggable Target for Pancreatic Cancer. Proceedings of the National Academy of Sciences of the United States of America, 110, 20723-20728. https://doi.org/10.1073/pnas.1314307110 |
| [43] | Zhou, C., Li, C., Luo, L., Li, X., Jia, K., He, N., et al. (2024) Anti-Tumor Efficacy of HRS-4642 and Its Potential Combination with Proteasome Inhibition in KRAS G12D-Mutant Cancer. Cancer Cell, 42, 1286-1300.e8. https://doi.org/10.1016/j.ccell.2024.06.001 |
| [44] | Zhou, C., Li, W., Song, Z., Zhang, Y., Zhang, Y., Huang, D., et al. (2023) LBA33 a First-in-Human Phase I Study of a Novel KRAS G12D Inhibitor HRS-4642 in Patients with Advanced Solid Tumors Harboring KRAS G12D Mutation. Annals of Oncology, 34, S1273. https://doi.org/10.1016/j.annonc.2023.10.025 |
| [45] | Jiang, L., Menard, M., Weller, C., Wang, Z., Burnett, L., Aronchik, I., et al. (2023) Abstract 526: RMC-9805, a First-in-Class, Mutant-Selective, Covalent and Oral KRASG12D(ON) Inhibitor That Induces Apoptosis and Drives Tumor Regression in Preclinical Models of KRASG12D Cancers. Cancer Research, 83, 526-526. https://doi.org/10.1158/1538-7445.am2023-526 |
| [46] | Ai, Q., Li, F., Zou, S., Zhang, Z., Jin, Y., Jiang, L., et al. (2023) Targeting KRASG12V Mutations with HLA Class II-Restricted TCR for the Immunotherapy in Solid Tumors. Frontiers in Immunology, 14, Article 1161538. https://doi.org/10.3389/fimmu.2023.1161538 |
| [47] | Koltun, E.S., Rice, M.A., Gustafson, W.C., Wilds, D., Jiang, J., Lee, B.J., et al. (2022) Abstract 3597: Direct Targeting of KRASG12X Mutant Cancers with RMC-6236, a First-in-Class, RAS-Selective, Orally Bioavailable, Tri-Complex RASMULTI(ON) Inhibitor. Cancer Research, 82, 3597-3597. https://doi.org/10.1158/1538-7445.am2022-3597 |
| [48] | Filis, P., Salgkamis, D., Matikas, A. and Zerdes, I. (2025) Breakthrough in RAS Targeting with Pan-RAS(ON) Inhibitors RMC-7977 and RMC-6236. Drug Discovery Today, 30, Article ID: 104250. https://doi.org/10.1016/j.drudis.2024.104250 |
| [49] | Kessler, D., Gerlach, D., Kraut, N. and McConnell, D.B. (2021) Targeting Son of Sevenless 1: The Pacemaker of KRAS. Current Opinion in Chemical Biology, 62, 109-118. https://doi.org/10.1016/j.cbpa.2021.02.014 |
| [50] | Winter, J.J.G., Anderson, M., Blades, K., Brassington, C., Breeze, A.L., Chresta, C., et al. (2015) Small Molecule Binding Sites on the Ras: SOS Complex Can Be Exploited for Inhibition of Ras Activation. Journal of Medicinal Chemistry, 58, 2265-2274. https://doi.org/10.1021/jm501660t |
| [51] | Sudhakar, N., Yan, L., Qiryaqos, F., Engstrom, L.D., Laguer, J., Calinisan, A., et al. (2024) The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading. Molecular Cancer Therapeutics, 23, 1418-1430. https://doi.org/10.1158/1535-7163.mct-23-0870 |
| [52] | Hofmann, M.H., Gmachl, M., Ramharter, J., Savarese, F., Gerlach, D., Marszalek, J.R., et al. (2021) BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition. Cancer Discovery, 11, 142-157. https://doi.org/10.1158/2159-8290.cd-20-0142 |
| [53] | Daley, B.R., Sealover, N.E., Finniff, B.A., Hughes, J.M., Sheffels, E., Gerlach, D., et al. (2025) SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma. Cancer Research, 85, 118-133. https://doi.org/10.1158/0008-5472.can-23-3256 |
| [54] | Thatikonda, V., Lyu, H., Jurado, S., Kostyrko, K., Bristow, C.A., Albrecht, C., et al. (2024) Co-Targeting SOS1 Enhances the Antitumor Effects of KRASG12C Inhibitors by Addressing Intrinsic and Acquired Resistance. Nature Cancer, 5, 1352-1370. https://doi.org/10.1038/s43018-024-00800-6 |
| [55] | Lu, X., Yu, R., Li, Z., Yang, M., Dai, J. and Liu, M. (2024) JC-010a, a Novel Selective SHP2 Allosteric Inhibitor, Overcomes RTK/Non-RTK-Mediated Drug Resistance in Multiple Oncogene-Addicted Cancers. Cancer Letters, 582, Article ID: 216517. https://doi.org/10.1016/j.canlet.2023.216517 |
| [56] | Fedele, C., Li, S., Teng, K.W., Foster, C.J.R., Peng, D., Ran, H., et al. (2021) SHP2 Inhibition Diminishes KRASG12C Cycling and Promotes Tumor Microenvironment Remodeling. Journal of Experimental Medicine, 218, e20201414. https://doi.org/10.1084/jem.20201414 |
| [57] | Nichols, R.J., Haderk, F., Stahlhut, C., Schulze, C.J., Hemmati, G., Wildes, D., et al. (2018) RAS Nucleotide Cycling Underlies the SHP2 Phosphatase Dependence of Mutant BRAF-, NF1-and RAS-Driven Cancers. Nature Cell Biology, 20, 1064-1073. https://doi.org/10.1038/s41556-018-0169-1 |
| [58] | Tanaka, N., Lin, J.J., Li, C., Ryan, M.B., Zhang, J., Kiedrowski, L.A., et al. (2021) Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation. Cancer Discovery, 11, 1913-1922. https://doi.org/10.1158/2159-8290.cd-21-0365 |
| [59] | Miyashita, H., Kato, S. and Hong, D.S. (2024) KRAS G12C Inhibitor Combination Therapies: Current Evidence and Challenge. Frontiers in Oncology, 14, Article 1380584. https://doi.org/10.3389/fonc.2024.1380584 |
