2. Academic Validation
  3. Inhibition of nicotinamide dinucleotide salvage pathway counters acquired and intrinsic poly(ADP-ribose) polymerase inhibitor resistance in high-grade serous ovarian cancer

Inhibition of nicotinamide dinucleotide salvage pathway counters acquired and intrinsic poly(ADP-ribose) polymerase inhibitor resistance in high-grade serous ovarian cancer

  • Sci Rep. 2023 Feb 27;13(1):3334. doi: 10.1038/s41598-023-30081-5.
Alexandre Sauriol 1 2,  Euridice Carmona 1 2,  Molly L Udaskin 3,  Nikolina Radulovich 3,  Kim Leclerc-Desaulniers 1 2,  Robert Rottapel 3 4,  Amit M Oza 3 5,  Stephanie Lheureux 3 5,  Diane M Provencher 1 2 6,  Anne-Marie Mes-Masson 7 8 9
Affiliations

Affiliations

  • 1 Centre de Recherche du Centre hospitalier de l'Université de Montréal, Montreal, QC, H2X 0A9, Canada.
  • 2 Institut du Cancer de Montréal, Montreal, QC, H2X 0A9, Canada.
  • 3 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
  • 4 Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
  • 5 Division of Medical Oncology and Hematology, University of Toronto, Toronto, ON, M5G 2M9, Canada.
  • 6 Division of Gynecologic Oncology, Université de Montréal, Montreal, QC, H3C 3J7, Canada.
  • 7 Centre de Recherche du Centre hospitalier de l'Université de Montréal, Montreal, QC, H2X 0A9, Canada. anne-marie.mes-masson@umontreal.ca.
  • 8 Institut du Cancer de Montréal, Montreal, QC, H2X 0A9, Canada. anne-marie.mes-masson@umontreal.ca.
  • 9 Department of Medicine, Université de Montréal, Montreal, QC, H3T 1J4, Canada. anne-marie.mes-masson@umontreal.ca.
PMID: 36849518 DOI: 10.1038/s41598-023-30081-5
Abstract

Epithelial ovarian Cancer is the most lethal gynecological malignancy, owing notably to its high rate of therapy-resistant recurrence in spite of good initial response to chemotherapy. Although poly(ADP-ribose) polymerase inhibitors (PARPi) have shown promise for ovarian Cancer treatment, extended therapy usually leads to acquired PARPi resistance. Here we explored a novel therapeutic option to counter this phenomenon, combining PARPi and inhibitors of nicotinamide phosphoribosyltransferase (NAMPT). Cell-based models of acquired PARPi resistance were created through an in vitro selection procedure. Using resistant cells, xenograft tumors were grown in immunodeficient mice, while Organoid models were generated from primary patient tumor samples. Intrinsically PARPi-resistant cell lines were also selected for analysis. Our results show that treatment with NAMPT inhibitors effectively sensitized all in vitro models to PARPi. Adding nicotinamide mononucleotide, the resulting NAMPT metabolite, abrogated the therapy-induced cell growth inhibition, demonstrating the specificity of the synergy. Treatment with olaparib (PARPi) and daporinad (NAMPT Inhibitor) depleted intracellular NAD+ , induced double-strand DNA breaks, and promoted Apoptosis as monitored by Caspase-3 cleavage. The two drugs were also synergistic in mouse xenograft models and clinically relevant patient-derived organoids. Therefore, in the context of PARPi resistance, NAMPT inhibition could offer a promising new option for ovarian Cancer patients.

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