Tubo-ovarian, high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy, with limited targeted therapies and poor outcomes. Heterozygous loss of RBX1 occurs in approximately 81% of HGSCs and drives chromosome instability and cellular transformation. Here, we identify CDK2 as a novel synthetic lethal (SL) interactor of RBX1 in clinically relevant RBX1 +/− fallopian tube secretory epithelial cell models. Genetic silencing or pharmacologic inhibition of CDK2 with siRNA duplexes or SNS-032, respectively, selectively reduced viability and induced cytotoxicity in RBX1 +/− cells, with significantly lower EC 50 values compared to controls. Importantly, in two malignant HGSC cell lines (COV362 and OVCAR-3), we further observed that CDK2 silencing or SNS-032 treatment in combination with RBX1 silencing induced significant reductions in cell numbers, thereby extending the SL interaction to established HGSC models. Mechanistically, SNS-032 treatment led to increased DNA double-strand breaks and apoptosis, as evidenced by increased numbers of γ-H2AX foci and cleaved Caspase-3 signal intensities. To our knowledge, this is the first demonstration of a SL interaction that exploits a heterozygous disease state in HGSC. These findings highlight CDK2 inhibition as a promising precision medicine strategy for RBX1 -deficient tumors, broaden the applicability of SL approaches beyond homozygous gene loss, and provide strong preclinical rationale for further therapeutic development.
Farrell et al. (2026) studied this question.