Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade

Cell. 2013 Dec 5;155(6):1309-22. doi: 10.1016/j.cell.2013.11.012.

Abstract

The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Antagonists / therapeutic use*
  • Androgen Receptor Antagonists / therapeutic use*
  • Animals
  • Disease Models, Animal
  • Drug Resistance, Neoplasm*
  • Gene Expression Regulation
  • Heterografts
  • Humans
  • Male
  • Mice
  • Neoplasm Transplantation
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / therapeutic use
  • Prostatic Neoplasms / drug therapy*
  • Receptors, Androgen / metabolism
  • Receptors, Glucocorticoid / metabolism*
  • Transcriptome

Substances

  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • MDV 3100
  • Receptors, Androgen
  • Receptors, Glucocorticoid
  • Phenylthiohydantoin

Associated data

  • GEO/GSE51497
  • GEO/GSE52169