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PARP inhibitor resistance: the underlying mechanisms and clinical implications

He Li1, Zhao-Yi Liu1, Nayiyuan Wu1

  • 1Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013, Hunan, People's Republic of China.

Molecular Cancer
|June 22, 2020
PubMed

Insights

PARP inhibitors (PARPi) are effective against BRCA1/2-deficient cancers, but resistance is common. This review details mechanisms of PARPi resistance and strategies to overcome it, focusing on homologous recombination repair restoration.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRCA1/2-deficient tumors exhibit synthetic lethality with PARP inhibitors (PARPi).
  • Approved PARPi are used for ovarian and breast cancers, but clinical resistance is frequent.
  • Over 40% of patients with BRCA1/2-deficient tumors do not respond to PARPi, and acquired resistance is common.

Purpose of the Study:

  • To review the mechanisms underlying PARP inhibitor resistance.
  • To summarize strategies for overcoming PARPi resistance and enhancing sensitivity.

Main Methods:

  • Literature review of studies on PARPi resistance mechanisms.
  • Analysis of factors contributing to resistance, including homologous recombination repair restoration and DNA replication fork protection.
  • Exploration of other resistance factors like reversion mutations and epigenetic modifications.

Main Results:

  • Homologous recombination repair restoration is a primary cause of PARPi resistance.
  • DNA replication fork protection also contributes to PARPi resistance in BRCA1/2-deficient cells.
  • Other factors include reversion mutations, epigenetic alterations, and pharmacological changes.

Conclusions:

  • Understanding the diverse mechanisms of PARPi resistance is crucial.
  • Developing strategies to counteract these mechanisms can improve treatment outcomes for patients with BRCA1/2-deficient cancers.
Keywords:
Homologous recombinationPARPiResistanceSynthetic lethality

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