Format

Send to

Choose Destination
Nat Commun. 2019 Jun 11;10(1):2556. doi: 10.1038/s41467-019-10460-1.

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

Author information

1
Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, QC, Canada.
2
Institut du cancer de Montréal, Montreal, H2X 0A9, QC, Canada.
3
Division of Gynecologic Oncology, Université de Montréal, Montreal, H3C 3J7, QC, Canada.
4
Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, QC, Canada. anne-marie.mes-masson@umontreal.ca.
5
Institut du cancer de Montréal, Montreal, H2X 0A9, QC, Canada. anne-marie.mes-masson@umontreal.ca.
6
Department of Medicine, Université de Montréal, Montreal, H3C 3J7, QC, Canada. anne-marie.mes-masson@umontreal.ca.
7
Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, QC, Canada. rodierf@mac.com.
8
Institut du cancer de Montréal, Montreal, H2X 0A9, QC, Canada. rodierf@mac.com.
9
Department of Radiology, Radio-Oncology and Nuclear Medicine, Université de Montréal, Montreal, H3C 3J7, QC, Canada. rodierf@mac.com.

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.

PMID:
31186408
DOI:
10.1038/s41467-019-10460-1

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center