KRAS G12C inhibitors in the treatment of metastatic colorectal cancer

KRAS mutations contribute substantially to the overall colorectal cancer burden and have long been a focus of drug development efforts. After a lengthy preclinical road, KRAS inhibition via the G12C allele has finally become a therapeutic reality. Unlike in NSCLC, early studies of KRAS inhibitors in CRC struggled to demonstrate single agent activity. Investigation into these tissue-specific treatment differences has led to a deeper understanding of the complexities of MAPK signaling and the diverse adaptive feedback responses to KRAS inhibition. EGFR reactivation has emerged as a principal resistance mechanism to KRAS inhibitor monotherapy. Thus, the field has pivoted to dual EGFR/KRAS blockade with promising efficacy. Despite significant strides in the treatment of KRAS G12C mutated CRC, new challenges are on the horizon. Alternative RTK reactivation and countless acquired molecular resistance mechanisms have shifted the treatment goalpost. This review focuses on the historical and contemporary clinical strategies of targeting KRAS G12C alterations in CRC and highlights future directions to overcome treatment challenges.