NRAS mutant E132K identified in young-onset sporadic colorectal cancer and the canonical mutants G12D and Q61K affect distinct oncogenic phenotypes.

Recent data show a global increase in colorectal cancer (CRC) cases among younger demographics, which portends poorer prognosis. The cause of rising incidence is uncertain, and its mutational landscape remains largely unexplored, including those in genes of the epidermal growth factor receptor pathway. Among these are NRAS mutants where there is paucity of functional studies compared to KRAS.

Non-Redundant and Overlapping Oncogenic Readouts of Non-Canonical and Novel Colorectal Cancer KRAS and NRAS Mutants.

RAS oncogene family members are molecular switches of signaling pathways that control cell growth, proliferation, differentiation, and survival. In colorectal cancer, Kirsten-RAS (KRAS) and neuroblastoma-RAS (NRAS) are the commonly mutated isoforms. Activating mutations in RAS result in cellular transformation independent of upregulated epidermal growth factor receptor (EGFR)-initiated signaling.

Phenotypic characterization of the novel, non-hotspot oncogenic KRAS mutants E31D and E63K.

KRAS proto-oncogene, GTPase (KRAS) functions as a molecular switch at the apex of multiple signaling pathways controlling cell proliferation, differentiation, migration, and survival. Canonical KRAS mutants, such as those in codons 12 and 13, produce constitutively active oncoproteins that short-circuit epidermal growth factor receptor (EGFR)-initiated signaling, resulting in dysregulated downstream effectors associated with cellular transformation. Therefore, anti-EGFR therapy provides little to no clinical benefit to patients with activating mutations.