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Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
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TLE3 loss confers AR inhibitor resistance by facilitating GR-mediated human prostate cancer cell growth

Sander Al Palit1, Daniel Vis1,2, Suzan Stelloo3

  • 1Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands.

Elife
|December 20, 2019
PubMed

Insights

Loss of TLE3 co-repressor causes resistance to prostate cancer therapies targeting the androgen receptor (AR). Restoring GR (glucocorticoid receptor) function promotes this resistance, offering new therapeutic targets.

Area of Science:

  • Molecular Oncology
  • Prostate Cancer Therapeutics
  • Gene Regulation

Background:

  • Androgen receptor (AR) inhibitors are standard treatments for prostate cancer.
  • Mechanisms of resistance to AR inhibitors are not fully understood.
  • The co-repressor TLE3's role in AR signaling and treatment resistance requires elucidation.

Purpose of the Study:

  • To investigate the role of TLE3 in mediating resistance to AR inhibitors in prostate cancer.
  • To identify molecular mechanisms linking TLE3 loss to treatment resistance.
  • To explore the potential of targeting glucocorticoid receptor (GR) in TLE3-mediated resistance.

Main Methods:

  • Genome-wide CRISPR-Cas9 screening in LNCaP prostate cancer cells.
  • Analysis of gene expression changes upon TLE3 loss and AR inhibition.
  • Chromatin immunoprecipitation (ChIP) to assess TLE3, AR, and GR binding at target gene loci.
  • Assessment of patient samples for TLE3 and GR expression levels.

Main Results:

  • Loss of TLE3 confers resistance to AR antagonists (apalutamide, enzalutamide).
  • TLE3 loss upregulates glucocorticoid receptor (GR) expression upon AR inhibition.
  • TLE3 and AR bind to the GR locus, and GR inhibition resensitizes resistant cells to enzalutamide.

Conclusions:

  • TLE3 loss promotes resistance to AR inhibitors through upregulation of GR.
  • A mechanistic link between TLE3, GR, and resistance to AR inhibitors in prostate cancer is established.
  • Targeting GR may overcome TLE3-mediated resistance to AR-targeted therapies.
Keywords:
EnzalutamideTLE3androgen receptorcancer biologyglucocorticoid receptorhumanprostate cancertherapy resistance

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