Targeted therapy for KRAS G12C-mutated colorectal cancer: advances, challenges, and future directions

Colorectal cancer (CRC) is among the most prevalent malignancies worldwide, with approximately 40% of the patients carrying KRAS mutations. Among these, the KRAS G12C mutation accounts for approximately 4% of the cases. This mutation introduces a unique cysteine residue at codon 12, enabling covalent binding and rendering KRAS G12C a tractable therapeutic target. Recently, selective small-molecule inhibitors of KRAS G12C, including sotorasib and adagrasib, have shown encouraging activity in early clinical trials, indicating potential clinical benefits for this subset of patients. However, their translation into routine clinical practice has been challenged by intrinsic and acquired resistance, treatment-related toxicities, and the absence of reliable predictive biomarkers. The aim of this study is to construct a clear knowledge framework that could inform the design of future clinical trials and optimize clinical practice. Future studies should focus on developing more potent next-generation inhibitors, exploring and optimizing rational combination strategies with other targeted agents or immunotherapies, investigating innovative therapeutic methods, and systematically identifying and validating predictive biomarkers. Collectively, with these efforts, we aim to enhance the efficacy, overcome resistance, and advance precision therapy for patients with KRAS G12C-mutant CRC.