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Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.
Shu, Shaokun; Lin, Charles Y; He, Housheng Hansen; Witwicki, Robert M; Tabassum, Doris P; Roberts, Justin M; Janiszewska, Michalina; Huh, Sung Jin; Liang, Yi; Ryan, Jeremy; Doherty, Ernest; Mohammed, Hisham; Guo, Hao; Stover, Daniel G; Ekram, Muhammad B; Brown, Jonathan; D'Santos, Clive; Krop, Ian E; Dillon, Deborah; McKeown, Michael; Ott, Christopher; Qi, Jun; Ni, Min; Rao, Prakash K; Duarte, Melissa; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Anders, Lars; Young, Richard A; Winer, Eric; Letai, Antony; Barry, William T; Carroll, Jason S; Long, Henry; Brown, Myles; Liu, X Shirley; Meyer, Clifford A; Bradner, James E; Polyak, Kornelia.
Afiliación
  • Shu S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Lin CY; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • He HH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Witwicki RM; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Tabassum DP; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Roberts JM; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Janiszewska M; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts USA.
  • Huh SJ; Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, M5G1L7, Canada.
  • Liang Y; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G2M9, Canada.
  • Ryan J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Doherty E; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Mohammed H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Guo H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Stover DG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Ekram MB; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Brown J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • D'Santos C; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Krop IE; Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, M5G1L7, Canada.
  • Dillon D; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • McKeown M; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Ott C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Qi J; Harvard University, Cambridge, Massachusetts, USA.
  • Ni M; Cancer Research UK, Cambridge Institute, University of Cambridge, UK, CB2 0RE.
  • Rao PK; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts USA.
  • Duarte M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Wu SY; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Chiang CM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Anders L; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Young RA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Winer E; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Letai A; Cancer Research UK, Cambridge Institute, University of Cambridge, UK, CB2 0RE.
  • Barry WT; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Carroll JS; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Long H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Brown M; Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
  • Liu XS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Meyer CA; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • Bradner JE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Polyak K; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Nature ; 529(7586): 413-417, 2016 Jan 21.
Article en En | MEDLINE | ID: mdl-26735014
ABSTRACT
Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.
Asunto(s)
Azepinas/farmacología; Azepinas/uso terapéutico; Resistencia a Antineoplásicos/efectos de los fármacos; Proteínas Nucleares/antagonistas & inhibidores; Estructura Terciaria de Proteína/efectos de los fármacos; Factores de Transcripción/antagonistas & inhibidores; Triazoles/farmacología; Triazoles/uso terapéutico; Neoplasias de la Mama Triple Negativas/tratamiento farmacológico; Animales; Unión Competitiva/efectos de los fármacos; Quinasa de la Caseína II/metabolismo; Proteínas de Ciclo Celular; Línea Celular Tumoral; Proliferación Celular/efectos de los fármacos; Proliferación Celular/genética; Cromatina/genética; Cromatina/metabolismo; Resistencia a Antineoplásicos/genética; Epigénesis Genética/efectos de los fármacos; Epigénesis Genética/genética; Femenino; Regulación Neoplásica de la Expresión Génica/efectos de los fármacos; Genoma Humano/efectos de los fármacos; Genoma Humano/genética; Humanos; Subunidad 1 del Complejo Mediador/metabolismo; Ratones; Proteínas Nucleares/deficiencia; Proteínas Nucleares/genética; Proteínas Nucleares/metabolismo; Fosforilación/efectos de los fármacos; Fosfoserina/metabolismo; Unión Proteica/efectos de los fármacos; Proteína Fosfatasa 2/metabolismo; Proteómica; Factores de Transcripción/deficiencia; Factores de Transcripción/genética; Factores de Transcripción/metabolismo; Transcripción Genética/efectos de los fármacos; Neoplasias de la Mama Triple Negativas/genética; Neoplasias de la Mama Triple Negativas/metabolismo; Neoplasias de la Mama Triple Negativas/patología; Ensayos Antitumor por Modelo de Xenoinjerto
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Azepinas / Factores de Transcripción / Triazoles / Proteínas Nucleares / Estructura Terciaria de Proteína / Resistencia a Antineoplásicos / Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Idioma: En Revista: Nature Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Azepinas / Factores de Transcripción / Triazoles / Proteínas Nucleares / Estructura Terciaria de Proteína / Resistencia a Antineoplásicos / Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Idioma: En Revista: Nature Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos