Abstract 2915: WRN depletion sensitizes the ARID1A-mutated cancers by inducing a distinct DNA damage response

Abstract SWI/SNF complex, which remodels chromatin structure to regulated transcription, is frequently mutated in various cancer types. ARID1A, a critical subunit of the SWI/SNF complex, is mutated in approximately 20% of colorectal cancers. Several synthetic lethal targets have been identified to address ARID1A-mutated cancers in various studies; ARID1B, EZH2, ATR, and AURKA-CDC25C. Notably, around 15% of ARID1A mutations are associated with microsatellite instability (MSI). In this study, we propose that WRN, already established as a synthetic lethal target of MSI cancers, is a promising therapeutic target in ARID1A-mutated cancers. In ARID1A-mutated cancer cells, WRN depletion reduced proliferation and increased apoptosis, underscoring its potential as a selective vulnerability. Interestingly, we observed distinct DNA damage response pathways triggered by WRN depletion depending on the presence of ARID1A mutations. In ARID1A wild type cells, WRN knockdown predominantly activated Chk1, whereas in ARID1A-mutated cells, Chk2 activation was more prominent. Further investigation revealed that ATR and Chk1 expression were downregulated in ARID1A-mutated cells. These findings suggest that Chk1 defects drive Chk2 activation in ARID1A-mutated cancers, presenting a distinct therapeutic opportunity to exploit this differential DNA damage response mechanism in ARID1A-mutated cancers. Citation Format: Jiwon Kim, Sung-Yup Cho. WRN depletion sensitizes the ARID1A-mutated cancers by inducing a distinct DNA damage response [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 2915.