All-trans retinoic acid sensitizes epithelial ovarian cancer to PARP inhibition after exposure to cisplatin.

Abstract

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.