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
  • 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. [email protected].
  • 5. Institut du cancer de Montréal, Montreal, H2X 0A9, QC, Canada. [email protected].
  • 6. Department of Medicine, Université de Montréal, Montreal, H3C 3J7, QC, Canada. [email protected].
  • 7. Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, QC, Canada. [email protected].
  • 8. Institut du cancer de Montréal, Montreal, H2X 0A9, QC, Canada. [email protected].
  • 9. Department of Radiology, Radio-Oncology and Nuclear Medicine, Université de Montréal, Montreal, H3C 3J7, QC, Canada. [email protected].
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.

Products