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

Article · Fleury H, Malaquin N, Tu V, Gilbert S, Martinez A, Olivier MA, Sauriol SA, Communal L, Leclerc-Desaulniers K, Carmona E, Provencher D, Mes-Masson AM, Rodier F

- Archive id: doi:10.1038/s41467-019-10460-1
- Published: 2019-06-11
- Venue: Nature communications
- DOI: https://doi.org/10.1038/s41467-019-10460-1
- PMID: 31186408
- PMCID: PMC6560032
- Citations: 195
- Source URL: https://doi.org/10.1038/s41467-019-10460-1
- PDF: https://europepmc.org/articles/PMC6560032/pdf
- Provenance: europepmc

## 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.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Biology of Aging & Longevity](https://space-kitty.com/topics/aging-longevity)

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