LAUSR

KRAS is the most frequently mutated oncogene in cancer. Tumor sequencing has revealed a complex spectrum of KRAS mutations across different cancer types, yet there is little understanding of how specific KRAS alterations impact tumor in initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R), and colon (KRASG13D) cancers. Induction of each mutation in the developing mouse pancreas reveals striking quantitative and qualitative differences in the degree of ductal transformation and premalignant progression. Further, using organoid models we show that KRASG13D mutants respond to EGFR inhibition, while the antiproliferative effect of KRASG12C-selective inhibitors can be overcome by upstream EGFR signaling. Together, these new mouse strains provide an ideal method for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers. This abstract is also being presented as Poster A41. Citation Format: Maria Paz Zafra, Direna Alonso-Curbelo, Sukanya Goswami, Emma M Schatoff, Teng Han, John E. Wilkinson, Lukas E. Dow. An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR06.