title: Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.
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.
authors: Human 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.
authors: Vivek K
authors: VK
authors: Arora
authors: Emily
authors: E
authors: Schenkein
authors: Rajmohan
authors: R
authors: Murali
authors: Sumit K
authors: SK
authors: Subudhi
authors: John
authors: J
authors: Wongvipat
authors: Minna D
authors: MD
authors: Balbas
authors: Neel
authors: N
authors: Shah
authors: Ling
authors: L
authors: Cai
authors: Eleni
authors: E
authors: Efstathiou
authors: Chris
authors: C
authors: Logothetis
authors: Deyou
authors: D
authors: Zheng
authors: Charles L
authors: CL
authors: Sawyers
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D010669:Phenylthiohydantoin; C540278:enzalutamide