Breakthroughs in KRAS G12C-mutant advanced colorectal cancer: from mechanisms to clinical practice
10.3760/cma.j.cn441530-441530-20250829-00321
- VernacularTitle:KRAS G12C突变型晚期结直肠癌的靶向治疗突破：机制探索与临床实践进展
- Author:
Jianling ZOU
1
;
Zhiyu CHEN
1
Author Information
1. 复旦大学附属肿瘤医院肿瘤内科 复旦大学上海医学院肿瘤学系，上海 200032
- Publication Type:Journal Article
- Keywords:
Colorectal neoplasms;
KRAS G12C mutation;
Inhibitor;
Drug resistance;
Combination therapy
- From:
Chinese Journal of Gastrointestinal Surgery
2025;28(11):1345-1349
- CountryChina
- Language:Chinese
-
Abstract:
KRAS 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.
