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

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Hubert Fleury1,2, Nicolas Malaquin1,2, Véronique Tu1,2

  • 1Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, H2X 0A9, QC, Canada.

Nature Communications
|June 13, 2019
PubMed

Insights

Poly(ADP-ribose) polymerase 1 inhibitors (PARPi) induce a reversible senescence in ovarian cancer cells. Combining PARPi with senolytic drugs offers a promising strategy to enhance cancer treatment and overcome resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Senescence

Background:

  • Senescence is a crucial tumor suppression mechanism characterized by stable cell cycle arrest.
  • The interplay between DNA repair pathways and poly(ADP-ribose) polymerase 1 inhibitors (PARPi) is a known synthetic lethal interaction in cancer therapy.

Purpose of the Study:

  • To investigate the role of PARPi in inducing p53-independent senescence in ovarian cancer cells.
  • To explore the reversibility of PARPi-induced senescence and its implications for sustained therapy.
  • To evaluate the potential of combining PARPi with senolytic drugs for enhanced cancer treatment.

Main Methods:

  • Induction of senescence in ovarian cancer cells using PARPi in combination with DNA repair triggers.
  • Characterization of senescence-associated phenotypic hallmarks (DNA-SCARS, inflammatory secretome, apoptosis resistance, proliferation restriction via Chk2 and p21).
  • Assessment of cell proliferation and response to drug withdrawal.
  • Evaluation of combination therapy with PARPi and senolytic drugs in preclinical cancer models.

Main Results:

  • PARPi and DNA repair triggers induce p53-independent senescence in ovarian cancer cells, marked by specific phenotypic hallmarks.
  • PARPi-induced senescence is reversible, with cells re-initiating proliferation upon drug withdrawal.
  • PARPi-senescent ovarian and breast cancer cells become susceptible to senolytic drugs.
  • Combination therapy of PARPi and senolytic drugs demonstrates efficacy in preclinical models of ovarian and breast cancer.

Conclusions:

  • PARPi can induce a transient, p53-independent senescence in cancer cells, offering a novel therapeutic window.
  • The reversibility of PARPi-induced senescence highlights the need for sustained or combination therapies.
  • Combining PARPi with senolytic drugs represents a rational and effective strategy to improve treatment outcomes and overcome drug resistance in ovarian and breast cancers.

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