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Resistance to PARP-Inhibitors in Cancer Therapy

Alicia Montoni1, Mihaela Robu, Emilie Pouliot

  • 1Laboratory for Skin Cancer Research, (CHU-Q) Hospital Research Centre of Laval University, Laval University Québec, QC, Canada.

Frontiers in Pharmacology
|March 2, 2013
PubMed

Insights

PARP inhibitors are effective cancer treatments, but cancer cells can develop resistance. This review explores how PARP inhibitors (PARPi) kill cancer cells and how resistance emerges, aiding in rationalizing their use.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Poly(ADP-ribose) polymerase (PARP) inhibitors show promise in cancer therapy.
  • PARP inhibitors (PARPi) are increasingly used as monotherapy or combination treatments.
  • Emerging resistance to PARPi necessitates understanding underlying mechanisms.

Purpose of the Study:

  • To review known and potential mechanisms of PARPi-induced cancer cell lethality.
  • To explore mechanisms of cancer cell resistance to PARPi.
  • To inform the rational use of PARPi in cancer treatment.

Main Methods:

  • Literature review of preclinical studies.
  • Analysis of clinical trial data.
  • Synthesis of proposed resistance mechanisms.

Main Results:

  • PARPi exert lethality through various mechanisms, including synthetic lethality in DNA repair-deficient cells.
  • Cancer cells develop resistance via alterations in drug target, drug efflux, or bypass pathways.
  • Multiple resistance mechanisms can coexist or be induced.

Conclusions:

  • Understanding PARPi efficacy and resistance is crucial for optimizing cancer therapy.
  • Targeting resistance mechanisms may overcome acquired resistance to PARPi.
  • Further research is needed to develop strategies to prevent or reverse PARPi resistance.
Keywords:
DNA damageDNA repairPARP-inhibitorspoly(ADP-ribose) polymerasepotentiation of anti-cancer therapyresistance to PARP-inhibitorssynthetic lethality

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