Precision Therapy in RAS Mutant Colorectal Cancer

Rat sarcoma virus (RAS) represents the most frequently mutated oncogene family across all malignancies and has therefore motivated decades of research aimed at understanding and targeting aberrant signaling elicited by oncogenic gain-of-function mutations. Of the 3 RAS genes (KRAS, NRAS, and HRAS), KRAS is most commonly mutated in pancreatic, colorectal, and lung adenocarcinomas, whereas NRAS and HRAS mutations are mostly found in selected hematologic malignancies, melanomas and thyroid cancers.1 In colorectal cancer (CRC), activating missense mutations in KRAS and NRAS have been reported at frequencies of approximately 40% and 4%, respectively, with more than 95% of mutations occurring in 1 of 3 major hotspots (residues G12, G13, and Q61). Non-G12 KRAS mutations are enriched in tumors of the right side of the colon, in those with microsatellite instability (MSI) and high tumor mutational burden.2 Interestingly, the overall frequency of KRAS mutations increases with age in microsatellite stable (MSS) CRC, particularly in males. In contrast, a reduced prevalence of KRAS mutations is observed in MSI/high mutational burden tumors in the elderly population.