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Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer.
Shah, Neel; Wang, Ping; Wongvipat, John; Karthaus, Wouter R; Abida, Wassim; Armenia, Joshua; Rockowitz, Shira; Drier, Yotam; Bernstein, Bradley E; Long, Henry W; Freedman, Matthew L; Arora, Vivek K; Zheng, Deyou; Sawyers, Charles L.
Afiliación
  • Shah N; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
  • Wang P; The Louis V. Gerstner Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
  • Wongvipat J; Department of Neurology, Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, United States.
  • Karthaus WR; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
  • Abida W; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
  • Armenia J; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States.
  • Rockowitz S; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
  • Drier Y; Department of Neurology, Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, United States.
  • Bernstein BE; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, United States.
  • Long HW; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, United States.
  • Freedman ML; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
  • Arora VK; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
  • Zheng D; Division of Medical Oncology, Washington University School of Medicine, St Louis, United States.
  • Sawyers CL; Department of Neurology, Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, United States.
Elife ; 62017 09 11.
Article en En | MEDLINE | ID: mdl-28891793
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Receptores de Glucocorticoides / Regulación Neoplásica de la Expresión Génica / Resistencia a Antineoplásicos / Antagonistas de Andrógenos Límite: Animals / Humans / Male Idioma: En Revista: Elife Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Receptores de Glucocorticoides / Regulación Neoplásica de la Expresión Génica / Resistencia a Antineoplásicos / Antagonistas de Andrógenos Límite: Animals / Humans / Male Idioma: En Revista: Elife Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido