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

• Published in: Nature communications Vol. 10; no. 1; pp. 2556 - 15
• Main Authors: Fleury, Hubert, Malaquin, Nicolas, Tu, Véronique, Gilbert, Sophie, Martinez, Aurélie, Olivier, Marc-Alexandre, Sauriol, Skye Alexandre, Communal, Laudine, Leclerc-Desaulniers, Kim, Carmona, Euridice, Provencher, Diane, Mes-Masson, Anne-Marie, Rodier, Francis
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.06.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: 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; Humans; Inflammation; Ovarian cancer; Ovarian Neoplasms - drug therapy; p53 Protein; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Ribose; Scars; Secretome; Senescence; Synthetic Lethal Mutations; Tumor suppression
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10460-1

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.