Enhanced Efficacy of Combined Therapy with Checkpoint Kinase 1 Inhibitor and Rucaparib via Regulation of Rad51 Expression in BRCA Wild-Type Epithelial Ovarian Cancer Cells

Purpose This study aimed to evaluate anticancer effects of combination treatment with poly(ADP-ribose) polymerase (PARP) and checkpoint kinase 1 (Chk1) inhibitors in BRCA wild-type ovarian cancer. PARP inhibitors can function as DNA-damaging agents in BRCA wild-type cancer, even if clinical activity is limited. Most epithelial ovarian cancers are characterized by a TP53 mutation caus-ing dysfunction at the G1/S checkpoint, which makes tumor cells highly dependent on Chk1-mediated G/M phase cell-cycle arrest for DNA repair. Materials and Methods We investigated the anticancer effects of combination treatment with prexasertib (LY2606368), a selective ATP competitive small molecule inhibitor of Chk1 and Chk2, and rucaparib, a PARP inhibitor, in BRCA wild-type ovarian cancer cell lines (OVCAR3 and SKOV3). Results We found that combined treatment significantly decreased cell viability in all cell lines and induced greater DNA damage and apoptosis than in the control and/or using monotherapies. Moreover, we found that prexasertib significantly inhibited homologous recombination-mediated DNA repair and thus showed a marked anticancer effect in combination treatment with rucaparib. The anticancer mechanism of prexasertib and rucaparib was considered to be caused by an impaired G2/M checkpoint due to prexas-ertib treatment, which forced mitotic catastrophe in the presence of rucaparib. Conclusion Our results suggest a novel effective therapeutic strategy for BRCA wild-type epithelial ovarian cancer using a combina-tion of Chk1 and PARP inhibitors.

Automated summary

The study evaluated the synergistic anticancer effects of combining PARP and Chk1 inhibitors in BRCA wild-type ovarian cancer, with promising results showing decreased cell viability and increased DNA damage and apoptosis. Prexasertib significantly inhibited homologous recombination-mediated DNA repair, leading to a marked anticancer effect when combined with rucaparib, suggesting a novel therapeutic strategy for BRCA wild-type ovarian cancer.