All-trans retinoic acid sensitizes epithelial ovarian cancer to PARP inhibition after exposure to cisplatin
Bingjie Mei, Junyang Li, Dengfeng Wang, Lu Feng, Jianming Huang, Guonan ZhangAbstract
Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Notably, Platinum-based chemotherapy induces resistance of EOC to poly (ADP-ribose) polymerase (PARP) inhibition. However, therapeutic approaches targeting PARP inhibitors (PARPi) resistance remain to be explored. Here, we show that all-trans retinoic acid (ATRA) reduces PARPi resistance-associated EOC cells induced by cisplatin (CDDP) treatment. Clinically applicable ATRA suppressed the outgrowth of CDDP-treated EOC cells both in vitro and in vivo. Moreover, a CDDP treatment followed by niraparib maintenance therapy in combination with ATRA improved the survival of EOC-bearing mice. These phenotypes correlated with PARPi resistant EOC signature, which consists of elevated expression of ALDH1A1, NAMPT, PARP1 and Chk1, as well as elevated NAD+ level-mediated high activity of ALDH1A1 and PARP1. Mechanistically, ATRA down-regulates the expression of these genes and level of intracellular NAD+. Our results suggest that ATRA in conjunction with PARPi represents a promising maintenance therapeutic strategy for EOC.