Abstract 431: Novel WRN drug resistant CDX models

Abstract Microsatellite Instability (MSI) is a condition characterized by the presence of mutations in microsatellite regions of DNA. This can lead to the accumulation of mutations in microsatellite regions, resulting in genomic instability and happened in various cancer types. Werner helicase (WRN) plays an important role in highly MSI (MSI-H) cancer cells and cause synthetic lethality when WRN was inhibited or knockout. Few WRN inhibitor like HRO761 and VVD-214 were revealed effectively killing the MSI-H cancer cells such as human colorectal cell lines HCT116 and SW48. In this study, to face the new unmet need that WRN inhibitors anti-cancer drugs may occurred, a WRN inhibitor resistant cell line against HRO761 and VVD-214 were established through the combination drug tolerance in vivo and in vitro was established. The drug resistant tumor tissues were collected after the in vivo drug resistance appeared as regrowth of tumors under 20 mg/kg HRO761 and 5 mg/kg VVD-214 treatment and dissected for primary cell culture to get the drug resistant cell line by escalating drug concentrations in vitro. The WRN inhibitors resistant cell lines were genotype and phenotype checked by STR and IC50 of cell growth when reached the drug resistant index more than 5 times of that of parental cells and indicated that different WRN inhibitors resistant HCT116 cell lines were successfully established and helpful for the discovery of anti-cancer drugs targeted on resistant to WRN inhibitors. Citation Format: Haiting Dai, Tiejun Bing, Huayi Qu, Huawei Pan, Wen-Jen Yu. Novel WRN drug resistant CDX models [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 431.