Advances in KRAS mutation inhibition in metastatic colorectal cancer

KRAS is the most frequently mutated oncogene in human malignancies, observed in approximately two in five colorectal cancers (CRC). KRAS mutations were historically considered “undruggable” ten years ago and associated with resistance to EGFR targeted therapy. The success of finding allele-specific covalent KRAS G12C inhibitors recently has made markedly breakthrough in KRAS targeted therapy, and has accelerated the discovery of agents targeting other KRAS mutants, such as G12D and G12V. Evidence in preclinical and clinical settings has proved excellent efficacy of several inhibitors in KRAS mutant CRC. Sotorasib and Adagrasib are currently changing the treatment paradigm for patients with metastatic CRC harboring KRAS G12C mutation. The phenomenon that KRAS G12C inhibition shows inferior efficacy in patients with CRC compared with non-small cell lung cancer has been observed in clinic due to drug resistance, and combination strategies to overcome the resistance are now being investigated in clinical trials. Here, we review the development of KRAS targeted treatment in CRC, mechanisms of resistance and potential combination strategies to improve efficacy.