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.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .
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Supplementary data

Supplementary Table 1

Lung metastatic lesions in mice

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Supplementary Figure 1

Growth inhibition of EOC cells with drug treatment.

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Supplementary Figure 2

The ALDH1A1 activity in EOC cells.

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Supplementary Figure 3

Expression of ALDH1A1, PARP1, NAMPT, and Chk1 in EOC cells treated with FK866 plus niraparib.

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Supplementary Figure 4

ATRA facilitates niraparib-induced apoptosis of EOC cells.

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Supplementary Figure 5

FK866 facilitates niraparib-induced apoptosis of EOC cells.

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Supplementary Figure 6

The images and weight of the tumor in vivo.

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Supplementary Figure 7

The mRNA expression of ALDH1A1, PARP1, NAMPT, Chk1 in EOC tumor tissues after treatment.

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Supplementary Figure 8

Evaluation of toxic and side effects in cisplatin treatment followed by niraparib combined with ATRA or FK866.

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