Abstract LB-134: A novel model to investigate Kras mutation specificity in the skin
Authors: Peter MK Westcott, Minh D. To, Reyno Delrosario, Kyle D. Halliwill, Peter Vuong, Melissa Q. McCreery, Allan Balmain
Journal: Cancer Research (2015)

Abstract The selection and specificity of mutations occurring in genes that drive cancer is a highly complex process that remains poorly understood for even the most well studied oncogenes. The specific pattern of RAS mutations across different cancers is thought to be modulated by differences in carcinogen exposure and metabolism, local DNA features and repair mechanisms, tissue-specific expression patterns and functional differences of the RAS isoforms1. Less is known about functional differences between the various activating mutations in RAS that may lead to selection of particular mutants in mouse or human cancers. Studies of mouse cancer models have provided evidence for strong genetic background effects on allele-specificity of Ras mutations2 as well as on selection of particular mutations at Kras codon 61 in lung adenomas3. We have also recently demonstrated a major role of germline Kras status in mutation selection during initiation, where carcinogen-induced lung tumors from Kras WT mice carry mostly (94%) Q61R Kras mutations, while those from Kras heterozygous mice carry mostly (92%) Q61L mutations4. In a M. Musculus (Mm) x M. Spretus (Ms) backcrossed population of HrasKO mice treated with DMBA/TPA, a model of Kras-driven tumorigenesis in the skin, we observed a wide spectrum of Kras mutations. Interestingly, genotype at the Kras locus significantly influenced Kras mutation specificity, with a switch from predominantly G13R mutations in Mm/Mm carcinomas to G12 and Q61L mutations in Mm/Ms carcinomas. Importantly, total Kras expression driven by the Mm Kras allele is higher than that driven by the Ms allele in the skin, and Kras mutations occur with high specificity for the Mm allele, suggesting that Q61L and G12 mutations may be suppressed by higher expression of the WT Kras allele in Kras Mm/Mm animals. We hypothesize that the ability of WT Kras to suppress certain mutants may be dependent on upstream activation by EGFR, and that this phenomenon may underlie the divergent responses to EGFR inhibition of colorectal cancer patients harboring Kras G12 versus G13 mutations5. Experiments to test this in mice by extended EGFR inhibition following carcinogen treatment are ongoing. References 1. Prior, I. A., Lewis, P. D. &amp; Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res 72, 2457-2467 (2012). 2. To, M. D. et al. A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice. Nat. Genet. 38, 926-30 (2006). 3. Dwyer-Nield, L. D. et al. Epistatic interactions govern chemically-induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J-ChrA/J chromosome substitution strains. Int J Cancer 126, 125-132 (2010). 4. Westcott, P. M. K. et al. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature (2014). doi:10.1038/nature13898 5. De Roock, W. et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304, 1812-20 (2010). Citation Format: Peter MK Westcott, Minh D. To, Reyno Delrosario, Kyle D. Halliwill, Peter Vuong, Melissa Q. McCreery, Allan Balmain. A novel model to investigate Kras mutation specificity in the skin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-134. doi:10.1158/1538-7445.AM2015-LB-134