KRAS is the most frequently mutated oncogene in cancer. Its activating mutations are associated with aggressive tumor behavior and resistance to certain therapies, including anti-EGFR treatments in colorectal cancer. In particular, the KRAS G12C mutation, which accounts for approximately 3–4% of colorectal cancers (CRCs) and 12–14% of non-small cell lung cancers (NSCLCs), involves a cysteine substitution at codon 12. This has provided the opportunity to develop selective covalent inhibitors that trap the mutant protein in its inactive state. The first targeted therapies for KRAS G12C-mutant cancers comprise sotorasib and adagrasib, both of which have been authorized for use in patients with previously treated NSCLC and CRC. Nevertheless, despite the evidence of clinical activity for this class of agents, primary and acquired resistance, dose optimization, and toxicity management remain significant open challenges. In this review, we summarize recent advances in KRASG12C tumor biology and pharmacological targeting. We also provide additional insights to guide future efforts to overcome the limitations of the current approaches and implement the treatment of KRASG12C-mutant cancers.
KRAS是癌症中最常发生突变的致癌基因。其激活突变与侵袭性肿瘤行为及对特定疗法（包括结直肠癌中的抗EGFR治疗）的耐药性相关。其中，KRAS G12C突变约占结直肠癌的3-4%和非小细胞肺癌的12-14%，该突变涉及第12密码子的半胱氨酸替换。这为开发选择性共价抑制剂提供了契机，此类抑制剂能将突变蛋白捕获于失活状态。针对KRAS G12C突变癌症的首批靶向疗法包括索托拉西布和阿达格拉西布，两者均已获批用于经治非小细胞肺癌和结直肠癌患者。然而，尽管这类药物显示出临床活性，原发性与获得性耐药、剂量优化及毒性管理仍是亟待解决的重大挑战。本综述总结了KRAS G12C肿瘤生物学及药物靶向研究的最新进展，并为未来克服现有方法局限、推进KRAS G12C突变癌症治疗提供了新的见解。
肿瘤(癌症)患者之家