Abstract 4153: CRISPR/Cas9-based oncogene editing enables characterization of rare mutations in cancer cells

Abstract

Abstract In the past decade new insights into key oncogenic pathways and the development of targeted therapies enabled the success of precision medicine. However, only a small part of the cancer genome can be targeted effectively. This is in part due to the fact that the number of cancer cell models for a given oncogenic mutation is limited. We hypothesized that CRISPR/Cas9-mediated genome editing may enhance the ability to functionally study rare genomic lesions or resistance mutations that arise in patients under therapy. As a proof of concept we established, genetically modified PC9 lung cancer cells that harbor an activating EGFR ex19 deletion (EGFRdel E746-A750) into double mutated (EGFRdel E746-A750+T790M) or triple mutated (EGFRdel E746-A750+T790M+C797S) EGFR in order to induce resistance against known EGFR inhibitors. These cell lines fully recapitulated the phenotypic response pattern to first and third generation EGFR inhibitors that have been observed in patients harboring these clinically relevant resistance mutations. In a next step we switched the dependency of PC9 cells from the intrinsic oncogenic EGFR mutation into a rare ex20 SVDins mutation (EGFRD770_N771insSVD) that is typically associated with resistance towards all known EGFR inhibitors. Again, we observed a shift in the response to targeted inhibition of EGFR when compared to parental cells. Since the methodological principles can be applied to an array on known oncogenic mutations our approach may serve as a versatile platform for the functional study of oncogenic mutations that are found in patients. We envision that such reprogrammed cells may be of use for the screening of novel targeted therapeutics and therefore may enable the development of mutation specific drugs that are currently lacking for the majority of patients. Citation Format: Dennis Plenker, Martin L. Sos. CRISPR/Cas9-based oncogene editing enables characterization of rare mutations in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4153. doi:10.1158/1538-7445.AM2017-4153