Abstract
Abstract Werner syndrome protein (WRN) is a RecQ-family helicase involved in the maintenance of genome integrity. Germline mutations in WRN cause premature aging and cancer predisposition. Analysis of systematic RNAi and CRISPR screening data has previously revealed that WRN is essential for the survival of cancer cell lines with high microsatellite instability (MSI-H). We have developed potent and selective small-molecule inhibitors of WRN helicase (WRNi) and showed that pharmacological inhibition of WRN causes lethality and induction of DNA damage markers selectively in MSI-H cancer cell lines compared to microsatellite-stable (MSS) cell lines. Screening of WRNi across a large panel of pooled, barcoded cell lines in the PRISM format revealed selective sensitivity in MSI-H cell lines and showed that pharmacological inhibition of WRN is highly correlated with genetic ablation of WRN across this panel, confirming selectivity for WRN. In vivo evaluation demonstrated robust and MSI-selective tumor regressions. These data provide pharmacological proof-of-concept for the WRN/MSI-H synthetic lethal relationship and support WRN inhibition as a novel therapeutic approach for the treatment of MSI-H cancers. Citation Format: Yanhua Rao, Anjana Srivatsan, Marya Liimatta, Diana Munoz, Jeanne Quirit, Jianxia Shi, An Nguyen, Xin Linghu, Federowicz Federowicz, Brian Jones, Melissa Fleury, Zach Newby, Michael P. Dillon, Paul A. Barsanti, Mark R. Lackner, Michael A. White, Yang Lee, Phil Landis, Yang Peng, Michelle Cicchini, Josh Cottom, Leng Nickels, Ed Brnardic, Michael DeMartino, Josh Taygerly. A small-molecule inhibitor of WRN selectively kills MSI-H cancer cells and phenocopies WRN genetic defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1628.
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