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All-trans Retinoic Acid Sensitizes Epithelial Ovarian Cancer to PARP Inhibition after Exposure to Cisplatin
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DOI：10.1158/1535-7163.MCT-24-0140.png)
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Abstract
En 中文
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 (CDDP). Notably, platinum-based chemotherapy induces resistance of EOC to PARP inhibition. However, therapeutic approaches targeting PARP inhibitor (PARPi) resistance remain to be explored. In this study, we show that all-trans retinoic acid (ATRA) reduces PARPi resistance-associated EOC cells induced by 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 the PARPi-resistant EOC signature, which consists of elevated expression of aldehyde dehydrogenase 1 family member A1, nicotinamide phosphoribosyltransferase, PARP1, and checkpoint kinase 1, as well as elevated NAD+ level-mediated high activity of aldehyde dehydrogenase 1 family member A1 and PARP1. Mechanistically, ATRA downregulates 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.
Keywords:
NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE
PHARMACOLOGICAL INHIBITION
REDUCES CHEMOTHERAPY
RESISTANCE
CELLS
EXPRESSION
THERAPY
BIOLOGY
NAMPT
CHK1
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