International Journal of Clinical Research

Ovarian cancer, the deadliest gynecological malignancy, faces significant challenges in treatment due to frequent drug resistance. PARP inhibitors like olaparib target DNA repair defects (e.g., BRCA mutations) to combat tumors, yet some patients show initial treatment resistance or rapid drug tolerance, with mechanisms remaining unclear. This study employed CRISPR-Cas9 genome-wide knockout screening to identify key genes regulating olaparib sensitivity in ovarian cancer cell lines, identifying ubiquitin-specific protease 10 (USP10) as a core regulatory factor. Functional validation demonstrated that USP10 knockout significantly enhances ovarian cancer cell sensitivity to olaparib, while overexpression induces drug resistance. Mechanistic analysis revealed that USP10 stabilizes DNA repair protein RAD51 through deubiquitination, activating the homologous recombination repair (HRR) pathway and counteracting olaparib-induced DNA damage accumulation. Clinical data showed strong correlation between high USP10 expression in ovarian cancer tissues and poor olaparib response and short progression-free survival. This study provides the first revelation of USP10's critical role in olaparib resistance, offering new theoretical foundations and experimental basis for optimizing PARP inhibitor strategies and developing combination therapy targets.

Ovarian cancer; CRISPR-Cas9 screening; USP10; PARP inhibitors