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Corrected on May 13, 2024.

Source: the publisher, via Crossref · checked Oct 20, 2026 · Read the notice (opens in a new tab)

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

Hubert Fleury, Nicolas Malaquin, Véronique Tu and 10 more (opens in a new tab)

Nature Communications · 2019 · CC BY

doi:10.1038/s41467-019-10460-1 (opens in a new tab)

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.

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