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 () and Francis Rodier ()
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Hubert Fleury: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Nicolas Malaquin: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Véronique Tu: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Sophie Gilbert: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Aurélie Martinez: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Marc-Alexandre Olivier: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Skye Alexandre Sauriol: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Laudine Communal: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Kim Leclerc-Desaulniers: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Euridice Carmona: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Diane Provencher: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Anne-Marie Mes-Masson: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)
Francis Rodier: Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10460-1

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DOI: 10.1038/s41467-019-10460-1

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