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

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

doi:10.1038/s41467-019-10460-1

Hubert Fleury, Anne-Marie Mes-Masson + Show 11 more

Open Access

https://doi.org/10.1038/s41467-019-10460-1

Copy DOI

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.

Highlights

Senescence is a tumor suppression mechanism defined by stable proliferation arrest
Poly(ADP-ribose) polymerase 1 (PARP1) plays an important role in DNA damage repair and PARP inhibitors (PARPi) have been explored as anticancer agents based on their ability to induce synthetic lethality in the context of homologous recombination (HR) deficiencies, such as those caused by BRCA1/2 mutations[1,2]
To explore the cellular mechanisms of action of poly(ADP-ribose) polymerase inhibitors (PARPi) we focus on cell fate decisions that we observed in high-grade serous epithelial ovarian cancer (HGSOC) cell lines reflecting a PARPi sensitivity spectrum[4]

Summary

Introduction

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 Chk[2] and p21 (CDKN1A). 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. Our data suggest that the clinical application of PARPi as maintenance therapy may favor recurrence and resistance by inducing a pharmacologically targetable inflammation-regulating reversible senescence-like state

Methods

Results

Conclusion