Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10460-1
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Funding
- ICM
- Canadian Institute for Health Research [CIHR MOP114962]
- Terry Fox Research Institute [TFRI 1030]
- Cancer Research Society (CRS)
- Ovarian Cancer Canada [20087, 22713]
- Fonds de recherche du Quebec -Sante (FRQS)
- CRS
- Genome Quebec
- IRICoR [265877]
- FRQS
- FRQS junior I-II career awards [22624, 33070]
- Banque de tissus et de donnees of the Reseau de recherche sur le cancer of the FRQS
- Canadian Tumor Repository Network (CTRNet)
- MITACS fellowship
- Oncopole
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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.
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