KRASG12C抑制剂在晚期结直肠癌治疗中的研究进展

doi:10.3760/cma.j.cn371439-20250225-00091

摘要/Abstract

摘要：

结直肠癌（CRC）是全球癌症相关死亡的主要原因之一。30%~40%的转移性CRC患者会发生KRAS基因突变，从而导致患者对抗表皮生长因子受体存在耐药性并且预后较差。针对KRAS的靶向治疗一直是研究的热点。近年来，KRAS^G12C突变抑制剂在实体瘤治疗中取得了良好的疗效。KRAS^G12C抑制剂可作为单一疗法或联合其他靶点抑制剂应用于KRAS^G12C突变转移性CRC。分析KRAS^G12C抑制剂在CRC中的研究进展具有重要意义，可为指导晚期CRC治疗提供参考。

关键词: 结直肠肿瘤, KRAS^G12C抑制剂, 分子靶向治疗

Abstract:

Colorectal cancer （CRC） remains a leading cause of cancer mortality globally. Mutations of the KRAS gene occur in 30%-40% of metastatic colorectal cancer patients， contributing to resistance to anti-epidermal growth factor receptor therapy and poor prognosis. Targeted therapy for KRAS has always been a research hotspot. In recent years， KRAS^G12C mutation inhibitors have achieved good efficacy in the treatment of solid tumors. KRAS^G12C inhibitors can be used as monotherapies and in combination with other targeted inhibitors for metastatic KRAS^G12C-mutant colorectal cancer. Analyzing the research progress of KRAS^G12C inhibitors in CRC is of great significance and can provide reference for guiding the treatment of advanced CRC.

Key words: Colorectal neoplasms, KRAS^G12C inhibitors, Molecular targete therapy

吴鑫, 任海朋. KRAS^G12C抑制剂在晚期结直肠癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2025, 52(8): 538-542.

Wu Xin, Ren Haipeng. Research progress of KRAS^G12C inhibitors in the treatment of advanced colorectal cancer[J]. Journal of International Oncology, 2025, 52(8): 538-542.

参考文献 39

[1]	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. DOI: 10.3322/caac.21834.
[2]	Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022[J]. CA Cancer J Clin, 2022, 72(1): 7-33. DOI: 10.3322/caac.21708.
[3]	Henry JT, Coker O, Chowdhury S, et al. Comprehensive clinical and molecular characterization of KRAS^G12C-mutant colorectal cancer[J]. JCO Precis Oncol, 2021, 5: PO. 20.00256. DOI: 10.1200/PO.20.00256.
[4]	Loong HH, Du N, Cheng C, et al. KRAS^G12C mutations in Asia: a landscape analysis of 11,951 Chinese tumor samples[J]. Transl Lung Cancer Res, 2020, 9(5): 1759-1769. DOI: 10.21037/tlcr-20-455.
[5]	Hong DS, Fakih MG, Strickler JH, et al. KRAS^G12C inhibition with sotorasib in advanced solid tumors[J]. N Engl J Med, 2020, 383(13): 1207-1217. DOI: 10.1056/NEJMoa1917239.
[6]	Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS^G12C[J]. N Engl J Med, 2023, 388(1): 44-54. DOI: 10.1056/NEJMoa2212419.
[7]	Jiang J, Jiang L, Maldonato BJ, et al. Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancers[J]. Cancer Discov, 2024, 14(6): 994-1017. DOI: 10.1158/2159-8290.CD-24-0027.
[8]	Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance[J]. J Cell Sci, 2016, 129(7): 1287-1292. DOI: 10.1242/jcs.182873. pmid: 26985062
[9]	Fruman DA, Chiu H, Hopkins BD, et al. The PI3K pathway in human disease[J]. Cell, 2017, 170(4): 605-635. DOI: 10.1016/j.cell.2017.07.029. pmid: 28802037
[10]	Yuan TL, Amzallag A, Bagni R, et al. Differential effector engagement by oncogenic KRAS[J]. Cell Rep, 2018, 22(7): 1889-1902. DOI: 10.1016/j.celrep.2018.01.051. pmid: 29444439
[11]	Takeda M, Yoshida S, Inoue T, et al. The role of KRAS mutations in colorectal cancer: biological insights, clinical implications, and future therapeutic perspectives[J]. Cancers (Basel), 2025, 17(3): 428. DOI: 10.3390/cancers17030428.
[12]	Papke B, Der CJ. Drugging RAS: know the enemy[J]. Science, 2017, 355(6330): 1158-1163. DOI: 10.1126/science.aam7622. pmid: 28302824
[13]	Ostrem JM, Peters U, Sos ML, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions[J]. Nature, 2013, 503(7477): 548-551. DOI: 10.1038/nature12796.
[14]	Liu J, Kang R, Tang D. The KRAS-G12C inhibitor: activity and resistance[J]. Cancer Gene Ther, 2022, 29(7): 875-878. DOI: 10.1038/s41417-021-00383-9.
[15]	Fakih MG, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRAS^G12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial[J]. Lancet Oncol, 2022, 23(1): 115-124. DOI: 10.1016/S1470-2045(21)00605-7.
[16]	Ou SI, Jänne PA, Leal TA, et al. First-in-human phase Ⅰ/ⅠB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS^G12C solid tumors (KRYSTAL-1)[J]. J Clin Oncol, 2022, 40(23): 2530-2538. DOI: 10.1200/JCO.21.02752.
[17]	Hallin J, Engstrom LD, Hargis L, et al. The KRAS^G12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients[J]. Cancer Discov, 2020, 10(1): 54-71. DOI: 10.1158/2159-8290.CD-19-1167. pmid: 31658955
[18]	Sacher A, LoRusso P, Patel MR, et al. Single-agent divarasib(GDC-6036) in solid tumors with a KRAS^G12C mutation[J]. N Engl J Med, 2023, 389(8): 710-721. DOI: 10.1056/NEJMoa2303810.
[19]	Zhou Q, Meng X, Sun L, et al. Efficacy and safety of KRAS^G12C inhibitor IBI351 monotherapy in patients with advanced NSCLC: results from a phase 2 pivotal study[J]. J Thorac Oncol, 2024, 19(12): 1630-1639. DOI: 10.1016/j.jtho.2024.08.005.
[20]	ClinicalTrials. Gov. An open-label, multi-center phase Ⅰ/Ⅱ clinical study evaluating the safety/tolerability, pharmacokinetics, and effectiveness of GFH925 in patients with advanced solid tumors with KRAS^G12C mutations[EB/OL]. [2024-11-26] [2025-04-08]. https://adisinsight.springer.com/trials/700341538.
[21]	ClinicalTrials. Gov. An open-label, multicenter, phase Ⅰb/Ⅲ study of efficacy and safety of IBI351 in combination with cetuximab in subjects with KRAS^G12C mutated metastatic colorectal cancer[EB/OL]. [2022-09-30] [2025-04-08]. https://clinicaltrials.gov/study/NCT05497336?term=NCT05497336&rank=1.
[22]	Amodio V, Yaeger R, Arcella P, et al. EGFR blockade reverts resistance to KRAS^G12C inhibition in colorectal cancer[J]. Cancer Discov, 2020, 10(8): 1129-1139. DOI: 10.1158/2159-8290.CD-20-0187. pmid: 32430388
[23]	Yaeger R, Mezzadra R, Sinopoli J, et al. Molecular characterization of acquired resistance to KRAS^G12C-EGFR inhibition in colorectal cancer[J]. Cancer Discov, 2023, 13(1): 41-55. DOI: 10.1158/2159-8290.CD-22-0405.
[24]	Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS^G12C[J]. N Engl J Med, 2023, 389(23): 2125-2139. DOI: 10.1056/NEJMoa2308795.
[25]	Yaeger R, Uboha NV, Pelster MS, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRAS^G12C-mutated metastatic colorectal cancer[J]. Cancer Discov, 2024, 14(6): 982-993. DOI: 10.1158/2159-8290.CD-24-0217. pmid: 38587856
[26]	Desai J, Alonso G, Kim SH, et al. Divarasib plus cetuximab in KRAS^G12C-positive colorectal cancer: a phase 1b trial[J]. Nat Med, 2024, 30(1): 271-278. DOI: 10.1038/s41591-023-02696-8.
[27]	ClinicalTrials. Gov. A phase 1/1b trial of MRTX849 in combination with BI 1701963 in patients with advanced solid tumors with KRAS^G12C mutation[EB/OL]. [2024-12-16] [2025-02-28]. https://clinicaltrials.gov/study/NCT04975256?term=NCT04975256&rank=1.
[28]	ClinicalTrials. Gov. A phase 1/2 trial of MRTX849 in combination with TNO155 in patients with advanced solid tumors with KRAS^G12C mutation KRYSTAL 2[EB/OL]. [2025-04-04] [2025-04-07]. https://clinicaltrials.gov/study/NCT04330664?term=NCT04330664&rank=1.
[29]	ClinicalTrials. Gov. Phase Ⅰ trial of adagrasib (MRTX849) in combination with cetuximab and irinotecan in patients with colorectal cancer[EB/OL]. [2025-03-10] [2025-04-07]. https://clinicaltrials.gov/study/NCT05722327?term=NCT05722327&rank=1.
[30]	ClinicalTrials. Gov. Study of sotorasib, panitumumab and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for treatment-naïve subjects with metastatic colorectal cancer with KRAS p.G12C mutation (CodeBreaK 301)[EB/OL]. [2025-04-04] [2025-04-07]. https://clinicaltrials.gov/study/NCT06252649?term=NCT06252649&rank=1.
[31]	Zhang J, Lim SM, Yu MR, et al. D3S-001, a KRAS^G12Cinhibitor with rapid target engagement kinetics, overcomes nucleotide cycling, and demonstrates robust preclinical and clinical activities[J]. Cancer Discov, 2024, 14(9): 1675-1698. DOI: 10.1158/2159-8290.CD-24-0006.
[32]	ClinicalTrials. Gov. A Phase 1/2, open label, dose-escalation, and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of D3S 001 monotherapy or combination therapy in subjects with advanced solid tumors with a KRAS p.G12C mutation[EB/OL]. [2025-04-08] [2025-04-08]. https://clinicaltrials.gov/study/NCT05410145?term=NCT05410145&rank=1.
[33]	马正红, 姜超. 非小细胞肺癌KRAS^G12C突变的研究进展[J]. 国际肿瘤学杂志, 2024, 51(2): 95-98. DOI: 10.3760/cma.j.cn371439-20231008-00013.
[34]	Stickler S, Rath B, Hamilton G. Targeting KRAS in pancreatic cancer[J]. Oncol Res, 2024, 32(5): 799-805. DOI: 10.32604/or.2024.045356. pmid: 38686056
[35]	Yang X, Wu H. RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms[J]. J Hematol Oncol, 2024, 17(1): 108. DOI: 10.1186/s13045-024-01631-9.
[36]	Awad MM, Liu S, Rybkin II, et al. Acquired resistance to KRAS^G12C inhibition in cancer[J]. N Engl J Med, 2021, 384(25): 2382-2393. DOI: 10.1056/NEJMoa2105281.
[37]	Ryan MB, Coker O, Sorokin A, et al. KRAS^G12C-independent feedback activation of wild-type RAS constrains KRAS^G12C inhibitor efficacy[J]. Cell Rep, 2022, 39(12): 110993. DOI: 10.1016/j.celrep.2022.110993.
[38]	Paniagua G, Jacob HKC, Brehey O, et al. KSR induces RAS-independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors[J]. Mol Oncol, 2022, 16(17): 3066-3081. DOI: 10.1002/1878-0261.13213.
[39]	Hu F, Lito P. Insights into how adeno-squamous transition drives KRAS inhibitor resistance[J]. Cancer Cell, 2024, 42(3): 330-332. DOI: 10.1016/j.ccell.2024.02.014. pmid: 38471455