Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors

◥ ARID1A is a subunit of SWI/SNF chromatin remodeling com-plexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium, including ovarian and uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). Loss-of-function mutations in ARID1A alter epigenetic regulation of transcription, cell-cycle checkpoint control, and DNA damage repair. We report here that mammalian cells with ARID1A deficiency harbor accumulated DNA base lesions and increased abasic (AP) sites, products of glycosylase in the first step of base excision repair (BER). ARID1A mutations also delayed recruitment kinetics of BER long-patch repair effectors. Although ARID1A-deficient tumors were not sensitive to monotherapy with DNA-methylating temozolomide (TMZ), the combination of TMZ with PARP inhibitors (PARPi) potently elicited double-strand DNA breaks, replication stress, and replication fork instability in ARID1A-deficient cells. The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A- mutated cancers to PARP inhibition, which warrants further exper-imental exploration and clinical trial validation. Significance: The combination of temozolomide and PARP inhibitor exploits the specific DNA damage repair status of ARID1A-inactivated ovarian cancers to suppress tumor growth.

Automated summary

ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is frequently mutated in various types of human cancers, especially those originating from endometrial epithelium. Loss-of-function mutations in ARID1A affect epigenetic regulation, cell-cycle checkpoint control, and DNA damage repair. This study demonstrates that ARID1A-deficient cells harbor DNA base lesions and impaired base excision repair. Furthermore, the combination of temozolomide and PARP inhibitors effectively induces DNA damage and suppresses tumor growth in ARID1A-mutated cancers.