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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells

Sylvie M Noordermeer1, Haico van Attikum2

  • 1Leiden University Medical Center, Department of Human Genetics, Einthovenweg 20, 2333 ZC Leiden, The Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands.

Trends in Cell Biology
|August 19, 2019
PubMed

Insights

Poly-(ADP)-ribose polymerase (PARP) inhibitors show promise for cancer treatment but face resistance. Understanding resistance mechanisms is key to developing new therapies for tumors with homologous recombination (HR) deficiencies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly-(ADP)-ribose polymerase (PARP) inhibitors are effective against tumors with homologous recombination (HR) deficiencies, such as those with BRCA1/2 mutations.
  • HR is a critical DNA double-strand break repair pathway, and its deficiency creates synthetic lethality with PARP inhibition.
  • Clinical resistance to PARP inhibitors (PARPi) is a significant challenge in cancer therapy.

Purpose of the Study:

  • To review and discuss the known mechanisms of PARPi resistance.
  • To highlight the insights gained from studying PARPi resistance into DNA repair and replication fork protection.
  • To explore potential novel therapeutic strategies targeting resistance mechanisms or acquired vulnerabilities.

Main Methods:

  • Literature review and synthesis of current research on PARPi resistance.
  • Analysis of established and emerging resistance mechanisms.
  • Discussion of the implications for cancer treatment.

Main Results:

  • Four primary mechanisms of PARPi resistance have been identified: altered drug availability, changes in (de)PARylation enzymes, restoration of HR function, and improved replication fork stability.
  • Studies on resistance have deepened our understanding of DNA double-strand break repair and replication fork protection pathways.
  • These insights offer a foundation for developing strategies to overcome or target PARPi resistance.

Conclusions:

  • PARPi resistance is multifactorial, involving complex alterations in DNA repair and drug response pathways.
  • Understanding these resistance mechanisms is crucial for improving the efficacy of PARPi in cancer treatment.
  • Targeting resistance pathways or exploiting acquired vulnerabilities presents a promising avenue for future therapeutic development.
Keywords:
BRCA1/2DNA double-strand break repairPARP inhibitor resistanceShieldincancerhomologous recombination

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