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A novel CRISPR-engineered prostate cancer cell line defines the AR-V transcriptome and identifies PARP inhibitor

Evangelia Kounatidou1, Sirintra Nakjang1, Stuart R C McCracken1

  • 1Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.

Nucleic Acids Research
|April 23, 2019
PubMed

Insights

Androgen receptor variants (AR-Vs) drive prostate cancer growth and resistance to therapy. Targeting PARP in AR-V positive cancers shows promise for synthetic lethality, offering new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate cancer (PC) resistance to androgen receptor (AR)-targeted therapies is a significant clinical challenge.
  • Tumor progression in advanced PC is driven by AR variants (AR-Vs), which are resistant to current treatments.
  • Distinguishing AR-V activity from full-length AR (FL-AR) has been difficult, limiting understanding of their function.

Purpose of the Study:

  • To develop a model system to isolate the function of AR-Vs from FL-AR.
  • To investigate the role of AR-Vs in driving tumor growth and gene expression.
  • To identify therapeutic vulnerabilities associated with AR-V activity.

Main Methods:

  • Development of a novel CRISPR-derived cell line (CWR22Rv1-AR-EK) lacking FL-AR but retaining AR-Vs.
  • Global transcriptomics to analyze gene expression changes driven by AR-Vs.
  • Investigation of AR-V interactions with DNA damage response proteins, specifically PARP1 and PARP2.

Main Results:

  • AR-Vs independently drive cell growth and androgenic gene expression in the absence of FL-AR.
  • AR-Vs upregulate a set of DNA damage response genes, and their depletion sensitizes cells to ionizing radiation.
  • AR-Vs interact with and depend on PARP1 and PARP2 for transcriptional activity.

Conclusions:

  • AR-Vs are key drivers of treatment resistance and tumor progression in prostate cancer.
  • A synthetic lethality exists between AR-Vs and PARP, suggesting a therapeutic strategy.
  • PARP inhibitors show potential for treating AR-V positive castration-resistant prostate cancer (CRPC).

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