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PARPi, BRCA, and gaps: controversies and future research

Diego Dibitetto1, Carmen A Widmer2, Sven Rottenberg3

  • 1Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland; Bern Center for Precision Medicine and Cancer Therapy Research Cluster, Department for Biomedical Research, University of Bern, 3012 Bern, Switzerland; Molecular Oncology and DNA Damage Response Laboratory, Department of Experimental Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy.

Trends in Cancer
|July 14, 2024
PubMed

Insights

Poly(ADP-ribose) polymerase inhibitors (PARPis) offer cancer treatment by exploiting homologous recombination deficiency. This review examines PARPi mechanisms, DNA polymerase theta

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerase inhibitors (PARPis) are approved cancer therapeutics targeting homologous recombination (HR) deficiency, often caused by BRCA1/2 mutations.
  • Understanding the synthetic lethality induced by PARPis in HR-deficient cancers is crucial for optimizing treatment strategies.

Purpose of the Study:

  • To review current debates and recent advancements in the application of PARPis for BRCA1/2-deficient cancers.
  • To analyze the 'double-strand break (DSB)' and 'single-stranded DNA (ssDNA) gap' models of PARPi-induced synthetic lethality.
  • To highlight the role of DNA polymerase theta (POLθ) and ssDNA gaps in therapeutic response and resistance.

Main Methods:

  • Comprehensive literature review of ongoing debates and recent breakthroughs in PARPi therapy.
  • Analysis of mechanistic models including DSB and ssDNA gap induction by PARPis.
  • Scrutiny of emerging research on DNA polymerase theta (POLθ) and its impact on therapy.

Main Results:

  • PARPi efficacy is complex, influenced by distinct synthetic lethality models and tumor heterogeneity.
  • Emerging evidence implicates DNA polymerase theta (POLθ) and ssDNA gaps in modulating responses to PARPi.
  • Mechanistic insights reveal potential drivers of PARPi resistance in BRCA-mutated cancers.

Conclusions:

  • Bridging the gap between laboratory findings and clinical outcomes requires further research into PARPi mechanisms.
  • Addressing tumor heterogeneity and resistance mechanisms is essential for improving PARPi efficacy in BRCA-mutated cancers.
  • Further investigation into the roles of POLθ and ssDNA gaps may reveal novel therapeutic strategies.
Keywords:
BRCADNA damagePARP inhibitorscancergapshomologous recombination

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