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Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer

Mohammad Asim1,2, Firas Tarish3,4, Heather I Zecchini5

  • 1Cancer Research UK Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK. mohammad.asim@cruk.cam.ac.uk.

Nature Communications
|August 31, 2017
PubMed

Insights

Androgen receptor (AR) is crucial for maintaining DNA repair in prostate cancer. Blocking AR and PARP together shows synthetic lethality, offering a new therapeutic strategy for advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Homologous recombination (HR) defects are observed in castration-resistant prostate cancers, making them sensitive to PARP inhibitors.
  • The role of the androgen receptor (AR) in maintaining HR integrity in prostate cancer is not fully understood.

Purpose of the Study:

  • To investigate the direct requirement of the androgen receptor (AR) in maintaining homologous recombination (HR) gene expression and activity in prostate cancer.
  • To explore the therapeutic potential of combining androgen-deprivation therapy (ADT) with PARP inhibitors in prostate cancer treatment.

Main Methods:

  • Assessing HR gene expression and activity in prostate cancer models.
  • Evaluating the impact of androgen-deprivation therapy (ADT) on PARP-mediated repair pathways.
  • Investigating the in vivo synthetic lethality between ADT and PARP inhibition.

Main Results:

  • The androgen receptor (AR) is directly required to maintain HR gene expression and activity in prostate cancer.
  • PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT).
  • Combined ADT and PARP inhibition demonstrate synthetic lethality in vivo, essential for prostate cancer cell survival.

Conclusions:

  • Androgen deprivation therapy (ADT) can functionally impair homologous recombination (HR) before castration resistance develops.
  • Combining ADT with PARP inhibitors upfront may be a viable therapeutic strategy for advanced or high-risk prostate cancer.
  • Targeting both AR and PARP is essential for effective treatment of high-risk prostate cancer.

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