Abstract B04: Activating K-RasA146T mutations induce Mapk-dependent hyperproliferation in the intestinal epithelium

Ras is the most commonly mutated oncogene in human cancer, and is highly mutated in pancreatic, lung, and colorectal cancer. The most commonly reported canonical activating point mutations occur in codons 12, 13, and 61. Colorectal cancer, in particular, harbors a number of noncanonical K-Ras mutations, including mutations at codon 146, which occur in ~4% of patients. To understand the biologic effects of K-Ras A146T expression in the intestinal epithelium and other tissues, we engineered a conditional Cre recombinase-dependent mutant allele ( K-Ras LSL-A146T ), expressed from the endogenous KRas locus. We crossed K-Ras LSL-A146T mice to Fabpl-Cre mice, which express Cre recombinase in the colonic and distal small intestinal epithelium, and compared the phenotype of Fabpl-Cre; K-Ras LSL-A146T/+ mice to that of Fabpl-Cre; K-Ras LSL-G12D/+ mice. Compared to K-Ras G12D , expression of K-Ras A146T results in a mild hyperplastic and hyperproliferative phenotype, while expression of K-Ras G12D causes drastic hyperplasia and hyperproliferation. Additionally, we found that K-Ras A146T expression activates Mapk signaling and that K-Ras A146T -induced hyperproliferation is Mapk-dependent. Interestingly, unlike Fabpl-Cre; K-Ras LSL-G12D mice, which lack Paneth cells in the small intestine, Fabpl-Cre; K-Ras LSL-A146T/+ mice have intact Paneth cells. Finally, we found that although K-Ras G12D expression in the pancreas causes neoplastic transformation, K-Ras A146T expression has no detectable effect on pancreatic homeostasis, even after one year. Together, our results suggest that compared to the canonical K-Ras G12D mutation, activating K-Ras A146T mutations have a similar but milder effect on colonic homeostasis. Additionally, consistent with human data, we found that K-Ras A146T mutations have tissue-specific effects on neoplastic transformation. Citation Format: Emily Poulin, Jessica Gierut, Kevin Haigis. Activating K-Ras A146T mutations induce Mapk-dependent hyperproliferation in the intestinal epithelium [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B04.