An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants María Paz, Zafra Marie J, Parsons Alonso-Curbelo, Direna Goswami, Sukanya Schatoff, Emma M. Han, Teng Katti, Alyna Calvo Fernandez, María Teresa Wilkinson, John E. Piskounova, Elena Dow, Lukas E. KRAS Pancreatic cancer Cancer-associated-mutations Organoids This work was supported by a project grant from the NIH/NCI under award R01CA195787. We thank the Weill Cornell Genomics Resource Core Facility who performed library preparation and sequencing for WES and RNA-seq. M.P. Zafra is supported in part by NCI Grant NIH T32 CA203702. 1. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York. United States 2. Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York. United States KRAS is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes affect tumor 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 allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Furthermore, using pancreatic organoid models, we show that KRASG13D mutants are sensitive to EGFR inhibition, whereas KRASG12C-mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers. Significance: KRAS is the most frequently mutated oncogene. Here, we describe new preclinical models that mimic tissue-selective KRAS mutations and show that each mutation has distinct cellular consequences in vivo and carries differential sensitivity to targeted therapeutic agents. 2026-01-15T13:28:57Z 2026-01-15T13:28:57Z 2020 journal article Maria Paz, Zafra et al. Cancer Discov (2020) 10 (11): 1654–1671. PMID: 32792368. doi:10.1158/2159-8290.CD-20-0442 PMID: 32792368 https://hdl.handle.net/10481/109763 10.1158/2159-8290.CD-20-0442 eng open access American Association for Cancer Research