Bevacizumab increases the sensitivity of olaparib to homologous recombination-proficient ovarian cancer by suppressing CRY1 via PI3K/AKT pathway

Abstract PARP inhibitors have changed the management of advanced high-grade epithelial ovarian cancer (EOC), especially homologous recombinant (HR)-deficient advanced high-grade EOC. However, the effect of PARP inhibitors on HR-proficient EOC is limited. Thus, new therapeutic strategy for HR-proficient EOC is desired. In recent clinical study, the combination of PARP inhibitors with anti-angiogenic agents improved therapeutic efficacy, even in HR-proficient cases. These data suggested that anti-angiogenic agents might potentiate EOC cells to PARP inhibitors. Here, we demonstrated that anti-angiogenic agents, bevacizumab and cediranib, increased the sensitivity of olaparib in HR-proficient EOC cells by suppressing HR activity. RNA sequencing showed that bevacizumab decreased the expression of CRY1 under DNA damage stress. We found that the anti-angiogenic agents suppressed the increase of CRY1 expression by inhibiting VEGF/CFGFR/PI3K pathway. The suppression of CRY1 expression resulted in decrease of HR activity. In addition, CRY1 inhibition also sensitized EOC cells to olaparib. These data suggested that anti-angiogenic agents and CRY1 inhibitors will be the promising candidate in the combination therapy with PARP inhibitors in HR-proficient EOC.