Nature Communications (Jun 2019)

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

  • Hubert Fleury,
  • Nicolas Malaquin,
  • Véronique Tu,
  • Sophie Gilbert,
  • Aurélie Martinez,
  • Marc-Alexandre Olivier,
  • Skye Alexandre Sauriol,
  • Laudine Communal,
  • Kim Leclerc-Desaulniers,
  • Euridice Carmona,
  • Diane Provencher,
  • Anne-Marie Mes-Masson,
  • Francis Rodier

DOI
https://doi.org/10.1038/s41467-019-10460-1
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 15

Abstract

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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.