Abstract LB-100: Systematic target prioritization and validation from genome-scale loss-of-function screens in large panels of human cancer cell lines

Abstract

Abstract Despite its increasing success and revolutionary impact on clinical oncology, Precision Cancer Medicine still has major roadblocks before it becomes applicable to a large proportion of patients. One such roadblock is the limited number of therapeutic targets available. Indeed, for the vast majority of cancer patients, we either do not know what their specific vulnerabilities are or do not have strategies to precisely target their vulnerabilities. In the Cancer Dependency Map Project (DepMap) at the Broad Institute, we aim to overcome these limitations through the use of genome-scale loss-of-function screens in a large panel of cancer cell lines combined with systematic molecular characterization of these cell lines. To date, we have conducted viability screens with genome-wide RNAi and CRISPR/Cas9 libraries on > 800 cell lines, all of which have also been comprehensively profiled with various omics approaches. In order to systematically identify and prioritize potential therapeutic targets, we created an analytical framework that uses a multifaceted approach to score gene dependencies based on the information extracted from screening outcomes, predictive models of sensitivity from all the genetic and molecular information, and the use of priors. To reproducibly validate the nominated targets, we also developed a toolbox of standardized assays that include confirmation of cell viability effects with orthogonal reagents/read-outs and efficient testing for in vivo efficacy across multiple cancer models. Using this approach, we have identified and validated several promising targets, including the WRN DNA helicase that is selectively essential in cancers with microsatellite instability (MSI). The data, framework, and toolbox developed here can inform the nomination and advancement of promising targets for drug development for Precision Cancer Medicine. Citation Format: Tsukasa Shibue, John M. Krill-Burger, Brenton R. Paolella, Benjamin Gaeta, Adhana Asfaw, Joshua M. Dempster, James M. McFarland, David E. Root, Jesse S. Boehm, Aviad Tsherniak, William C. Hahn, Francisca Vazquez. Systematic target prioritization and validation from genome-scale loss-of-function screens in large panels of human cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-100.