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

Abstract

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.