Abstract A039: RAS signaling strength determines phenotypic response in the colon

Abstract The RAS (KRAS, NRAS and HRAS) genes are the most frequently mutated in cancer and are highly specific to tissue type by isoform and codon, yet the underlying cause for this selection is unknown. Mutations in KRAS, but not NRAS, frequently occur and act as oncogenic events in colorectal cancer. Biochemically, activating mutations in RAS increase the abundance of the GTP-bound active state, however, the position and substitution of the mutated amino acid affect the ‘on’ and ‘off’ rates of the RAS-GTP/GDP cycle. Alterations in codon 61 result in the largest accumulation of RAS-GTP. While this leads to robust pathway activation, codon 61 mutations are rarely observed in KRAS-mutant colorectal cancers. To study the effect of the isoform and codon mutations in colorectal tumor formation, we engineered mouse models to express codon 12 or 61 mutations in Kras and Nras. Our mouse models recapitulate the clinical RAS isoform and allelic selection. We found Kras G12D provided the greatest proliferative effect. To further understand this allelic selection, we investigated the interplay between RAS signaling strength and intestinal epithelial cell composition. We observed a correlation between RAS signaling strength and induction of stem cell differentiation. Together, our data provide insights to the preference for KRAS mutations in human colorectal cancers and provides a rationale for allelic selection. Citation Format: Amanda R. Moore, Sandra Melo Carlos, Elaine E. Storm, Lisa M. McGinnis, Shiva Malek, Frederic J. de Sauvage. RAS signaling strength determines phenotypic response in the colon [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A039.