Introduction/Background Theoretically, PARP inhibitors can function as a DNA damaging agents in BRCA wild type cancer, even if the clinical activity is limited. Most of epithelial ovarian cancer is characterized by TP53 mutation causing dysfunction in the G1/S checkpoint, which makes tumor cells highly dependent on Chk1-mediated G/M phase cell cycle arrest for DNA repair. Therefore, we hypothesized that combination treatment of PARP inhibitors (Rucaparib) and Chk1 inhibitor (LY2606368) would be active in BRCA wild type epithelial ovarian cancer.
Methodology We investigated the anticancer effects of combination treatment with prexasertib (LY2606368) and rucaparib, in BRCA wild type ovarian cancer cell lines (OVCAR3 and SKOV3) using clinically attainable concentrations.
Results We found that combination treatment synergistically decrease cell viability in all cell lines and induces greater DNA damage and apoptosis than the control and/or monotherapies. Moreover, we identified that prexasertib can significantly inhibit homologous recombination (HR) mediated DNA repair and thus showed marked synergistic anticancer effect in combination treatment with PARP inhibitor. The synergy between prexasertib and rucaparib was considered to be caused by impaired G2/M checkpoint due to prexasertib treatment, which forced mitotic catastrophe in the presence of rucaparib.
Conclusion According to our data, prexasertib and rucaparib combination showed synergistic anticancer effects against BRCA wild type epithelial ovarian cancer cells through reduced Rad51 foci formation and greater induction of apoptosis. This might be a novel effective therapeutic strategy for BRCA-wild type epithelial ovarian cancer.
Disclosure Nothing to disclose.
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