Characterization of K-Ras(G13D) as a unique activating allele in a mouse model of colorectal cancer.

The K-RAS (Kirsten rat sarcoma) oncoprotein is mutationally activated in ~40% of colorectal cancers (CRCs), and K-RAS mutation state is an excellent predictor of the failure of a cancer to respond to conventional chemotherapy or targeted therapy. The colonic epithelium provides a biologically interesting context in which to study the allele-specific characteristics of K-RAS, because CRC displays a broad spectrum of activating mutations that occur at lower frequencies than K-RAS-mutant tumors of other organs. Of particular interest to us, activating G\u003eD mutations in codon 13 of K-RAS occur in 10-20% of K-RAS-mutant CRC, are biochemically distinct from the G12D mutation in mechanism of RAS activation, and have a different epidemiologic profile in patient survival. We established a novel mouse model to compare the colon phenotype of the K-RasG13D allele to that of the previously characterized K-RasG12D allele. In the context of homeostasis and colorectal cancer, we characterized the murine colonic epithelium at histologic, proteomic and transcriptomic levels. Ultimately, we aim to elucidate mutant-specific drug sensitivities by deeply understanding K-Ras biology in the genetically controlled setting of our mouse models. Citation Format: Yi-Jang Lin, Patrick Dischinger, Carrie Graveel, Matthew Steensma, Kevin M. Haigis. Characterization of K-RasG13D as a unique activating allele in a mouse model of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A18.