Abstract 1897: Systematic methods to identify cancer vulnerabilities from genome-wide loss-of-function screens: An interactive framework for target discovery

Abstract

Abstract Over a thousand genome-scale loss-of-function screens have been performed, as part of efforts such as The Cancer Dependency Map (DepMap), to establish the landscape of genetic dependencies across a diverse set of cancer cell lines. A key challenge to using this resource for therapeutic target discovery is discerning common or tissue-related gene dependencies from those that represent true cancer-specific vulnerabilities. Although many successful cancer-specific targets have been identified by synthetic lethality with patient-prevalent driver mutations, the number of novel synthetic lethals identified as more cancer cell lines are screened has been limited compared to the total number of newly observed selective dependencies. Better understanding of how these selective dependencies are connected to molecular features of the sensitive cell lines could unlock a wealth of potential targets. As part of the DepMap project at the Broad Institute, we created a software pipeline and interactive web-tool for researchers to interrogate the compendium of CRISPR and RNAi screens and systematically rank potential targets by several key factors, most notably selectivity, disease indication, and predictability from multi-omics features (WES, RNAseq, methylation, proteomics). A strength of our framework is the ability to explore the relationships between a dependency and its top predictive features since this could provide insights into the mechanism underlying the cellular dependency and aid in generating therapeutic hypotheses. Additionally, users can perform disease-specific analyses and incorporate annotations for small molecule tractability or drug availability. We anticipate this tool will lower the barrier to systematic genome-wide target discovery using DepMap and provide insights into strategies and best practices for nominating promising targets. Citation Format: John M. Krill-Burger, Ashir A. Borah, Brenton R. Paolella, James M. McFarland, Francisca Vazquez. Systematic methods to identify cancer vulnerabilities from genome-wide loss-of-function screens: An interactive framework for target discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1897.