Abstract 3095: Comparative analysis of WRN inhibitors HRO761 and VVD-133214 in a cancer cell panel: insights into MSI status-dependent drug responses

Abstract High-throughput screening of a cancer cell panel represents a pivotal instrument in the armamentarium of drug discovery and development. The sensitivity profiles of these cell lines serve as a cornerstone for the refinement of in vivo model systems and for the stratification of patient cohorts in clinical trials. Werner Syndrome RecQ Helicase (WRN), a member of the RecQ helicase family, is instrumental in the preservation of genomic integrity. Its multifaceted role encompasses DNA repair, replication, recombination, and telomere maintenance. WRN has garnered significant attention as a potential therapeutic nexus in oncology, particularly within the context of tumors exhibiting microsatellite instability (MSI). The synthetic lethality between WRN and MSI has been the subject of intensive research, demonstrating that WRN inhibition is selectively toxic to cancer cells harboring a high microsatellite instability (MSI-H) phenotype, which is a characteristic observed across a spectrum of malignancies, including colorectal, endometrial, and gastric cancers. The present investigation assesses the therapeutic potential of two advanced WRN inhibitors, HRO761 and VVD-133214, within a meticulously curated panel of cancer cells that display a continuum of MSI and microsatellite-stable (MSS) statuses, as well as HRO761 resistant cell lines. Employing cell viability assays, we conducted a comparative analysis of the growth-inhibitory effects of these compounds on MSI and MSS cell lines. Our data reveal a pronounced anti-neoplastic effect of both HRO761 and VVD-133214 in some MSI-H cell lines, juxtaposed with a diminished impact on MSS cell lines. Further, transcriptomic profiling elucidated discrete transcriptional landscapes modulated by each inhibitor, shedding light on their divergent pharmacological mechanisms. This study not only showcases our proficiency in high-throughput screening and bioinformatics but also contributes a wealth of knowledge regarding the MSI-dependent therapeutic responses to WRN-targeted agents, potentially informing future clinical strategies in cancer treatment. Citation Format: Lili Chai, Tingting Yang, Huawei Pan, Wei Liu, Zhengtai Li, Xiaojian Wang, Tj (Tiejun) Bing. Comparative analysis of WRN inhibitors HRO761 and VVD-133214 in a cancer cell panel: insights into MSI status-dependent drug responses [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 3095.