{"id":"doi:10.1038/s41467-019-10460-1","kind":"article","title":"Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence","authors":["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"],"author_count":13,"year":2019,"published":"2019-06-11","venue":"Nature communications","cited_by":195,"doi":"10.1038/s41467-019-10460-1","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-019-10460-1","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-019-10460-1","updated":null,"pmid":"31186408","pmcid":"PMC6560032","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC6560032/pdf","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_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence\" by Fleury H, Malaquin N, Tu V et al., https://doi.org/10.1038/s41467-019-10460-1, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"aging-longevity","name":"Biology of Aging & Longevity","domain_slug":"medicine"}],"cited_in_dossiers":[]}