• Vivek K Arora, Emily Schenkein, Rajmohan Murali, Sumit K Subudhi, John Wongvipat, Minna D Balbas, Neel Shah, Ling Cai, Eleni Efstathiou, Chris Logothetis, Deyou Zheng, and Charles L Sawyers.
• 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.
• Cell. 2013 Dec 5;155(6):1309-22.

AbstractThe 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.Copyright © 2013 Elsevier Inc. All rights reserved.

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