Emerging Therapeutic Strategies for Non-G12C KRAS Mutations in Colorectal Cancer: Focusing on G12D and G12V.

KRAS mutations are present in approximately 40-45% of colorectal cancers (CRC), but currently approved KRAS-directed therapies address only the small G12C subset. G12D and G12V account for a much larger proportion of KRAS-mutant CRC and remain major unmet therapeutic targets. This review summarizes emerging strategies for non-G12C KRAS-mutant CRC. Current preclinical, translational, and early clinical evidence was narratively synthesized, focusing on allele-specific G12D and G12V inhibitors, pan-RAS approaches, upstream SOS1/SHP2 co-targeting, anti-EGFR combinations, immune-based strategies, and tissue and circulating tumor DNA profiling.

The development of MRTX1133, zoldonrasib (RMC-9805), VS-7375, RMC-5127, and daraxonrasib (RMC-6236) demonstrates that direct targeting of previously undruggable KRAS alleles is becoming clinically feasible. In CRC, however, EGFR-mediated feedback reactivation of wild-type RAS remains a central resistance mechanism, making anti-EGFR combination strategies particularly important.Tissue and circulating tumor DNA profiling may support patient selection, monitoring of clonal evolution, and characterization of acquired resistance. The non-G12C KRAS era is beginning, but durable benefit in CRC will likely require rational combinations tailored to allele, lineage, and resistance biology.