RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer

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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Published on: August 12, 2015

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Chenkui Miao1,2, Takuya Tsujino1,3, Tomoaki Takai1,3

  • 1Division of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Science Advances
|February 18, 2022
PubMed

Insights

Loss of RNASEH2B in prostate cancer sensitizes cells to PARP inhibitors. However, co-deletion with RB1 causes resistance, which BRCA2 loss can reverse, guiding PARP inhibitor therapy.

Area of Science:

  • Genomic alterations in prostate cancer
  • Targeted cancer therapies
  • DNA repair mechanisms

Background:

  • Current cancer therapies often focus on single gene mutations, neglecting combined genomic alterations.
  • Prostate cancer exhibits complex genomic profiles impacting treatment efficacy.
  • Poly(ADP-ribose) polymerase (PARP) inhibitors are a key targeted therapy.

Purpose of the Study:

  • To investigate the impact of co-occurring deletions of RNASEH2B, RB1, and BRCA2 on prostate cancer sensitivity to PARP inhibition.
  • To elucidate the molecular mechanisms underlying resistance and resensitization to PARP inhibitors.
  • To explore potential therapeutic strategies to overcome PARP inhibitor resistance.

Main Methods:

  • Analysis of concurrent genomic alterations in prostate cancer, focusing on chromosome 13q deletions.
  • Assessment of cancer cell sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition.
  • Investigation of DNA repair pathways, including ribonucleotide excision repair and homologous recombination repair.
  • Evaluation of ATR inhibition as a strategy to overcome PARP inhibitor resistance.

Main Results:

  • Deletion of RNASEH2B confers sensitivity to PARP inhibition via impaired ribonucleotide excision repair and PARP trapping.
  • Co-deletion of RNASEH2B and RB1 leads to PARP inhibitor resistance through E2F1-induced BRCA2 expression and enhanced homologous recombination repair.
  • Loss of BRCA2 in RNASEH2B/RB1 co-deleted cells restores sensitivity to PARP inhibition.
  • ATR inhibition can counteract E2F1-induced BRCA2 expression, overcoming RB1 loss-mediated PARP inhibitor resistance.

Conclusions:

  • Interactions between multiple genomic alterations significantly influence response to PARP inhibitors in prostate cancer.
  • Comprehensive genomic testing is crucial for identifying patients who may benefit from PARP inhibition.
  • ATR inhibition presents a potential therapeutic approach to overcome PARP inhibitor resistance in specific genetic contexts.

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