Genome-wide CRISPR-based screening reveals ABCG2 as a novel drug resistance gene in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers and incidence is increasing due to the increase in risk factors such as diabetes and obesity. One reason for the high mortality rate associated with this cancer is the high rate of resistance to commonly used chemotherapies. Our previous work showed a link between patient survival and expression of drug resistance genes, thus we undertook genome-wide CRISPR knockout and activation screens to identify genes conferring resistance to cytotoxic chemotherapies in two pancreatic cancer cell lines. Our screen revealed hundreds of genes with potential roles in drug resistance, many of which have expression levels that correlate with patient survival. We have validated our top candidates by stably expressing individual guide RNAs in each of three pancreatic cell lines, Panc-1, BxPC-3 and MiaPaCa-2 and screening for viability following treatment with three chemotherapeutic agents, oxaliplatin, gemcitabine, and irinotecan. ABCG2, an ABC transporter, was revealed as our top hit, conferring resistance to multiple drugs in multiple cell lines. Our results would suggest that repression of ABCG2 might improve sensitivity to cytotoxic chemotherapies. We test this hypothesis using an ABCG2 inhibitor and demonstrate the effect of this inhibitor on cell viability, drug sensitivity and transcriptomic profiles in the context of cell lines with variable ABCG2 expression. Note: This abstract was not presented at the meeting. Citation Format: Ryne C. Ramaker, Andrew A. Hardigan, Emily R. Gordon, Richard M. Myers, Sara J. Cooper. Genome-wide CRISPR-based screening reveals ABCG2 as a novel drug resistance gene in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5135.