Emerging and Established Targets in Colorectal Cancer: Translating Biology Into Therapeutics

Alterations in the mitogen-activated protein kinase (MAPK) pathway play a central role in colorectal cancer (CRC) tumor biology, therapeutic response, and resistance. RAS oncogenic mutations are present in up to 35% of CRC; they represent constitutively active molecular switches that impair GTP hydrolysis and promote ligand-independent signaling. The development of allele-specific KRAS G12C inhibitors exploits a cryptic pocket to trap the protein in its inactive (OFF) conformation. In metastatic CRC, where EGFR feedback loop limits monotherapy efficacy, combinations of KRAS G12C inhibitors with EGFR blockade and chemotherapy have demonstrated meaningful activity. Parallel efforts allowed the development of RAS(ON) inhibitors that sterically block the interaction with downstream effectors. Co-occurring genomic alterations, MAPK pathway reactivation, and pharmacologic limitations drive primary and acquired resistance. BRAF V600 mutations drive approximately 10% of CRCs; first-generation, type I BRAF inhibitors require combination with upstream EGFR, downstream MEK/ERK blockade to overcome adaptive feedback reactivation. Emerging strategies include paradox breaking RAF inhibitors, type II pan-RAS inhibitors, and immunotherapy combinations, particularly relevant for the immune-activated phenotype of BRAF-mutant microsatellite stable tumors. Beyond RAS and RAF, novel therapeutic avenues (such as antibody-drug conjugates, bispecific antibodies, DNA damage response inhibitors, and tumor microenvironment modulating agents) are reshaping precision oncology in CRC. Integrating multiomics profiling with dynamic biomarkers may enable durable activity and personalized treatment strategies.