Abstract 6393: Patient selection, target engagement and pharmacodynamic markers of WRN inhibitor GSK4418959 (IDE275)

Abstract GSK4418959 (IDE275) is a clinical-stage WRN helicase inhibitor designed to treat MSI-H cancer. This compound phenocopies WRN genetic inactivation, with exquisite MSI-H selectivity in large panel of cell lines. Results from extensive cell line profiling indicate a strong correlation between MSI score and sensitivity to the compound. Interestingly, sensitivity to the compound also correlates with the TA-repeat prevalence of individual cell lines. There appears to be no bias toward specific genetic mutations in the dMMR panel, and the compound's sensitivity is not affected by the driver mutation status of the tested cell lines or models. These findings support the use of dMMR and MSI-H as patient-selection biomarkers for GSK4418959 (IDE275). A mass spectrometry-based target occupancy assay was developed to measure WRN target engagement by GSK4418959 (IDE275), using a covalent WRN inhibitor as a probe. GSK4418959 (IDE275) demonstrated dose-dependent target occupancy in cells, showing that over 90% target occupancy is required to inhibit growth. This assay was successfully applied to xenograft tumors, demonstrating dose-dependent WRN occupancy by GSK4418959 (IDE275) in vivo. GSK4418959 (IDE275) induced significant DNA damage selectively in MSI-H cells, but not in MSS cells. DNA damage markers such as gH2AX and pKAP1 were strongly induced both in vitro and in vivo. Immunohistochemistry (IHC) results suggested dose- and time-dependent induction of these markers in MSI-H xenograft models by GSK4418959 (IDE275), providing evidence to support their use in monitoring drug response in clinical settings. Citation Format: Yanhua Rao, Gabriele Picco, Diana M. Munoz, Susan Merrihew, Yang Lee, Anjana Srivatsan, Marya Liimatta, Yang Peng, Thomas E. Angel, Robert Silvers, Joshua E. Cottom, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Raynold Shenje, Brian T. Jones, Edward J. Brnardic, Michael P. DeMartino, Geeta Sharma, Mathew J. Garnett, Joshua P. Taygerly, Michael A. White, Benjamin Schwartz. Patient selection, target engagement and pharmacodynamic markers of WRN inhibitor GSK4418959 (IDE275) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6393.