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Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade

Vivek K Arora1, Emily Schenkein, Rajmohan Murali

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Cell
|December 10, 2013
PubMed

Insights

Novel therapies for advanced prostate cancer can lead to resistance. Glucocorticoid receptor (GR) activation by dexamethasone confers resistance to enzalutamide by substituting for the androgen receptor (AR).

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Advanced prostate cancer treatment has been revolutionized by antiandrogen therapies like enzalutamide.
  • Drug resistance remains a significant challenge in managing advanced prostate cancer.

Purpose of the Study:

  • To investigate the mechanisms underlying resistance to antiandrogen therapy in advanced prostate cancer.
  • To identify novel therapeutic targets for overcoming treatment resistance.

Main Methods:

  • Utilized a credentialed preclinical model of advanced prostate cancer.
  • Analyzed patient tumor samples to confirm findings.
  • Investigated the role of glucocorticoid receptor (GR) expression and function.

Main Results:

  • Induction of glucocorticoid receptor (GR) expression was a common feature in drug-resistant tumors.
  • GR substituted for the androgen receptor (AR) to maintain the resistant phenotype.
  • Dexamethasone (a GR agonist) conferred enzalutamide resistance, while a GR antagonist restored sensitivity.

Conclusions:

  • Glucocorticoid receptor (GR) upregulation is a key mechanism of escape from androgen receptor (AR) blockade in prostate cancer.
  • Targeting GR may offer a strategy to restore sensitivity to antiandrogen therapies.
  • AR inhibition can lead to GR upregulation, driving resistance through an alternative nuclear receptor pathway.

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