摘要KRAS突变是人类肿瘤中最常见的致癌驱动事件之一。在结直肠癌（CRC）中，35%~49%的病例存在 KRAS突变，其中3%~4%为第12密码子甘氨酸突变为半胱氨酸的 KRAS G12C亚型。与其他 KRAS突变相比， G12C突变常提示标准治疗反应不佳及总生存期缩短。近年来，多款KRAS G12C抑制剂进入临床开发，Ⅰ期和Ⅱ期研究已显示出积极疗效；Ⅲ期CodeBreaK 300研究进一步证实，索托拉西布联合帕尼单抗较标准治疗显著改善疗效，并成为 KRAS G12C突变型转移性CRC的新治疗标准。然而，耐药性问题仍不可避免，其机制涉及信号通路反馈激活、继发性突变及上皮-间质转化等多层次过程。通过靶向旁路及上下游节点、开发新型（K）RAS抑制剂、探索新的特异性降解剂以及多机制、多靶点的联合策略正成为研究热点。本文系统回顾KRAS G12C抑制剂在转移性CRC中的发展历程，总结耐药机制，并探讨新型联合方案的潜力，以期为未来治疗优化提供理论依据与研究方向。

abstractsKRAS mutations are major oncogenic drivers in colorectal cancer (CRC), occurring in 35%-49% of cases; of which 3%-4% involve the KRAS G12C subtypes, characterized by a glycine-to-cysteine substitution at codon 12. This variant is associated with poor treatment response and reduced overall survival. Recent phase I/II trials of KRAS G12C inhibitors have shown promising results, and the phase III CodeBreaK 300 study confirmed that sotorasib combined with panitumumab significantly improved efficacy compared with standard treatment, establishing a new therapeutic option for KRAS G12C-mutant metastatic CRC. However, drug resistance inevitably develops, driven by mechanisms such as feedback activation of signaling pathways, secondary mutations, and epithelial-mesenchymal transition. Strategies under investigation include targeting alternative signaling pathways, developing next-generation inhibitors and specific degraders, and exploring multi-mechanism or multi-target combination strategies. This review systematically outlines the development of KRAS G12C inhibitors in mCRC, summarizes resistance mechanisms, and discusses emerging combination regimens, aiming to provide a theoretical basis and future directions for treatment optimization.