Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer
Neel Shah,
Ping Wang,
John Wongvipat,
Wouter R Karthaus,
Wassim Abida,
Joshua Armenia,
Shira Rockowitz,
Yotam Drier,
Bradley E Bernstein,
Henry W Long,
Matthew L Freedman,
Vivek K Arora,
Deyou Zheng,
Charles L Sawyers
Affiliations
Neel Shah
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States; The Louis V. Gerstner Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
Ping Wang
Department of Neurology, Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, United States
John Wongvipat
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
Wouter R Karthaus
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
Wassim Abida
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States
Joshua Armenia
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
Shira Rockowitz
Department of Neurology, Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, United States
Yotam Drier
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, United States
Bradley E Bernstein
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, United States
Henry W Long
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States
Matthew L Freedman
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, United States
In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.
