Abstract 3136: X-MAN™ isogenic DualXenoTM models with KRAS mutation predicts the effect of anti-EGFR agents

Abstract

Abstract We have previously reported using cell lines generated with Horizon Discovery's rAAV-based GENESIS™ gene editing platform to establish a comprehensive list of isogenic cancer models for in vivo compound screening, with mutations in a wide variety of genes including KRAS, PIK3CA, PTEN, IDH1 and IDH2, and p53. These isogenic tumor models comprise pairs of cell lines which share the same genetic background, differing only by the mutation of interest, and therefore allow definitive studies of specific genetic variances to be performed. In the current study we developed a DualXenoTM method where isogenic pairs of a colorectal cell line, one of each pair with a KRAS mutation, were inoculated simultaneously in the two flanks of the same mouse. The tumors were then treated with EGFR targeted therapeutics to address the question of resistant phenotypes elicited by different KRAS mutations. This design allows direct comparison of wild type and mutant isogenic pairs for treatment responses that are associated with the defined genetic variations. Our results demonstrated that tumors harboring the G12V mutation were resistant to both Cetuximab and Erlotinib treatment, while tumors harboring the G13D mutation remained sensitive to both agents. This is in consistent with clinical findings (De Roock, et al. JAMA 2010, 304(16), pp 1812), and our own findings with PDX mouse clinical trials in colon cancer, suggesting that the KRAS G13D mutation may establish a different signaling network to other KRAS mutations, and that colon cancer patients with the mutation should not be excluded from the EGFR targeted therapies. Citation Format: Yanmei Sun, Songling Zhang, Nan Li, Holly Astley, Rebecca Foster, Christine Schofield, Chris Chris Torrance, Jinying Ning, Qian Shi. X-MAN™ isogenic DualXenoTM models with KRAS mutation predicts the effect of anti-EGFR agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3136. doi:10.1158/1538-7445.AM2014-3136