KRAS-targeted therapies in colorectal cancer: a systematic analysis of mutations, inhibitors, and clinical trials

Cancer research · Colorectal cancer · KRAS

KRAS mutations occur in over one‑third of colorectal cancers and recent drug development has produced specific inhibitors that are now in clinical use and investigation, offering a promising therapeutic strategy for KRAS‑mutant colorectal cancer.

KRAS mutations occur in over one-third of colorectal cancers (CRC), primarily affecting codons 12 and 13, and less frequently codons 61, 117, and 146. Rare mutations in other codons have been reported, but often lack clear functional significance. These mutations activate pathways that drive cell proliferation, impair differentiation, and suppress apoptosis. KRAS-mutant CRCs are associated with poorer prognosis, higher recurrence rates, reduced chemotherapy response, and resistance to EGFR-targeted therapies. Stratifying patients by KRAS mutation status is now standard for guiding treatment, though not all mutations confer the same oncogenicity or therapeutic response. Once considered undruggable, recent advances have led to the development of inhibitors targeting specific KRAS mutant isoforms. Consequently, precise characterization of KRAS mutational profiles is critical to optimize treatment strategies in CRC. This study provides a systematic analysis of KRAS mutation frequency and co-occurrence, reviews current targeted therapies, and examines ongoing clinical trials for the most prevalent KRAS alterations in CRC.

KRAS-driven colorectal cancers exhibit aggressive behavior and resistance to standard therapies. The emergence of allele‑specific inhibitors that can directly target KRAS mutations offers a novel therapeutic approach that could improve survival and quality of life for patients whose tumors harbor these common alterations.

Evidence level: Megerősített klinikai bizonyíték. Több vagy erősebb humán vizsgálat támogatja.

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