Journal Article

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

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

2019

Overview

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. Senescence induction is known to induce stable proliferation arrest. Here, the authors show that sustained PARP inhibition promotes a reversible p53-independent senescence, and that PARP inhibition is synthetic lethal when combined with senolytic agents in pre-clinical models of ovarian and breast cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/2 / 13/31 / 13/51 / 14/1 / 14/34 / 14/63 / 38/109 / 38/77 / 38/89 / 45/41 / 631/67 / 631/67/1059 / 631/67/327 / 631/80 / 631/80/82 / 64/60 / 82/29 / Adenosine diphosphate / Antineoplastic Agents - pharmacology / Apoptosis / Bcl-x protein / Breast cancer / Breast Neoplasms - drug therapy / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Cellular Senescence / Deoxyribonucleic acid / DNA / DNA Repair / Drug Resistance, Neoplasm / Female / Humanities and Social Sciences / Humans / Inflammation / multidisciplinary / Ovarian cancer / Ovarian Neoplasms - drug therapy / p53 Protein / Poly(ADP-ribose) / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Ribose / Scars / Science / Science (multidisciplinary) / Secretome / Senescence / Synthetic Lethal Mutations / Tumor suppression