Abstract 2106: Creating a living public oncology drug resource using PRISM cell line viability screening

Abstract

Abstract Cancer treatment options are rapidly expanding, with many new targeted agents and therapeutic modalities under development. However, systematic characterization of the cellular effects of emerging drug candidates is limited. Screening such agents against the approximately 900 diverse cancer cell lines in the PRISM assay can provide insights into drug specificity and cancer subtype selectivity and, leveraging the rich genomic and functional characterization of PRISM cell lines, support for annotated mechanisms of action. Our goal was to generate a large, high-quality, oncology-focused dataset that can benefit the cancer research community by characterizing new test agents of high clinical relevance. In the past year, this effort has been utilized to screen a total of 180 test agents with plans to extend testing to an additional 140 over the next year. The collection includes biologics (e.g., cytokines, antibodies, antibody-drug conjugates), targeted protein degraders, and small molecules. Supporting the quality of the screening collection and the robustness of the PRISM assay, the majority of inhibitors (including mutant-selective KRAS inhibitors, and inhibitors targeting the WRN helicase, a preferential vulnerability in cancers with microsatellite instability) tested to date closely mimic the effects of genetic knockout and/or knockdown of their annotated target, as measured by CRISPR and shRNA data available through the Dependency Map Portal (depmap.org). Further, while we observe strong modality-independent co-clustering of test agents annotated to act on the same target(s) (e.g., tucatinib with the antibody-drug conjugates T-DM1 and T-DXd for HER2), intriguing differences in efficacy and selectivity emerge in individual cell line models. All PRISM reference screening data and analyses will be made publicly available through depmap.org to serve as a benchmark for new drug development candidates and to further the efforts of researchers worldwide to match emerging cancer therapies to the patients most likely to benefit. Citation Format: Matthew G. Rees, Mustafa Kocak, Claudine Mapa, Dennie Frederick, Ellen Nguyen, Alvin Kalathungal, Anthony Fazio, John F. Davis, Emily Reeves, Ariah Tucci, Rachael Barry, Colleen Harrington, Jillian Eskra, Melissa M. Ronan, William R. Sellers, Jennifer A. Roth. Creating a living public oncology drug resource using PRISM cell line viability screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2106.