Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence.
Nat Commun
; 10(1): 2556, 2019 06 11.
Article
em En
| MEDLINE
| ID: mdl-31186408
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Senescência Celular
/
Proliferação de Células
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Reparo do DNA
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Inibidores de Poli(ADP-Ribose) Polimerases
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Mutações Sintéticas Letais
Limite:
Female
/
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article