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Mechanisms of resistance to PARP inhibitors - an evolving challenge in oncology

Angela Mweempwa1, Michelle K Wilson1

  • 1Cancer and Blood, Auckland City Hospital, Auckland 1023, New Zealand.

Cancer Drug Resistance (Alhambra, Calif.)
|May 18, 2022
PubMed

Insights

Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) show promise in treating BRCA-mutated cancers. Understanding PARPi resistance mechanisms is crucial for developing effective combination therapies to improve patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) exploit synthetic lethality in cancers with BRCA mutations or homologous recombination deficiency.
  • Four PARPi are FDA-approved for ovarian and breast cancers, with emerging data in pancreatic and prostate cancers.

Purpose of the Study:

  • To review the mechanisms of resistance to PARPi.
  • To discuss strategies for early detection of PARPi resistance.

Main Methods:

  • Literature review of studies on PARPi resistance mechanisms.
  • Analysis of established and emerging resistance pathways.

Main Results:

  • Key resistance mechanisms include restoration of homologous recombination, alterations in PARP1, suppression of non-homologous end joining, and changes in replication fork protection or drug concentration.
  • Understanding these mechanisms is vital for overcoming treatment limitations.

Conclusions:

  • Identifying and understanding PARPi resistance mechanisms can guide the development of novel combination therapies.
  • Early detection of resistance is essential for timely therapeutic adjustments and improved treatment efficacy.
Keywords:
BRCA reversionPoly-adenosine diphosphate ribose polymerase inhibitionhomologous recombinationovarian cancerresistance mechanisms

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