2. Academic Validation
  3. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence

Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence

  • Nat Commun. 2019 Jun 11;10(1):2556. doi: 10.1038/s41467-019-10460-1.
Hubert Fleury 1 2,  Nicolas Malaquin 1 2,  Véronique Tu 1 2,  Sophie Gilbert 1 2,  Aurélie Martinez 1 2,  Marc-Alexandre Olivier 1 2,  Alexandre Sauriol 1 2,  Laudine Communal 1 2,  Kim Leclerc-Desaulniers 1 2,  Euridice Carmona 1 2,  Diane Provencher 1 2 3,  Anne-Marie Mes-Masson 4 5 6,  Francis Rodier 7 8 9
Affiliations

Affiliations

  • 1 Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, QC, Canada.
  • 2 Institut du cancer de Montréal, Montreal, H2X 0A9, QC, Canada.
  • 3 Division of Gynecologic Oncology, Université de Montréal, Montreal, H3C 3J7, QC, Canada.
  • 4 Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, QC, Canada. anne-marie.mes-masson@umontreal.ca.
  • 5 Institut du cancer de Montréal, Montreal, H2X 0A9, QC, Canada. anne-marie.mes-masson@umontreal.ca.
  • 6 Department of Medicine, Université de Montréal, Montreal, H3C 3J7, QC, Canada. anne-marie.mes-masson@umontreal.ca.
  • 7 Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, QC, Canada. rodierf@mac.com.
  • 8 Institut du cancer de Montréal, Montreal, H2X 0A9, QC, Canada. rodierf@mac.com.
  • 9 Department of Radiology, Radio-Oncology and Nuclear Medicine, Université de Montréal, Montreal, H3C 3J7, QC, Canada. rodierf@mac.com.
PMID: 31186408 DOI: 10.1038/s41467-019-10460-1
Abstract

Senescence is a tumor suppression mechanism defined by stable proliferation arrest. Here we demonstrate that the known synthetic lethal interaction between poly(ADP-ribose) polymerase 1 inhibitors (PARPi) and DNA repair triggers p53-independent ovarian Cancer cell senescence defined by senescence-associated phenotypic hallmarks including DNA-SCARS, inflammatory secretome, Bcl-XL-mediated Apoptosis resistance, and proliferation restriction via Chk2 and p21 (CDKN1A). The concept of senescence as irreversible remains controversial and here we show that PARPi-senescent cells re-initiate proliferation upon drug withdrawal, potentially explaining the requirement for sustained PARPi therapy in the clinic. Importantly, PARPi-induced senescence renders ovarian and breast Cancer cells transiently susceptible to second-phase synthetic lethal approaches targeting the senescence state using senolytic drugs. The combination of PARPi and a senolytic is effective in preclinical models of ovarian and breast Cancer suggesting that coupling these synthetic lethalities provides a rational approach to their clinical use and may together be more effective in limiting resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16106
    99.89%, PARP Inhibitor