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Genetic Heterogeneity of BRAF Fusion Kinases in Melanoma Affects Drug Responses.
Botton, Thomas; Talevich, Eric; Mishra, Vivek Kumar; Zhang, Tongwu; Shain, A Hunter; Berquet, Céline; Gagnon, Alexander; Judson, Robert L; Ballotti, Robert; Ribas, Antoni; Herlyn, Meenhard; Rocchi, Stéphane; Brown, Kevin M; Hayward, Nicholas K; Yeh, Iwei; Bastian, Boris C.
Afiliação
  • Botton T; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, C
  • Talevich E; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, C
  • Mishra VK; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, C
  • Zhang T; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MA 20892, USA.
  • Shain AH; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, C
  • Berquet C; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, C
  • Gagnon A; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, C
  • Judson RL; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA.
  • Ballotti R; U1065, Institut National de la Santé et de la Recherche Médicale, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, 06200 Nice, France.
  • Ribas A; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Herlyn M; Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.
  • Rocchi S; U1065, Institut National de la Santé et de la Recherche Médicale, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, 06200 Nice, France.
  • Brown KM; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MA 20892, USA.
  • Hayward NK; Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
  • Yeh I; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, C
  • Bastian BC; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, C
Cell Rep ; 29(3): 573-588.e7, 2019 10 15.
Article em En | MEDLINE | ID: mdl-31618628
ABSTRACT
BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation αC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Fusão Oncogênica / Resistencia a Medicamentos Antineoplásicos / Proteínas Proto-Oncogênicas B-raf / Melanoma Limite: Animals / Female / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Fusão Oncogênica / Resistencia a Medicamentos Antineoplásicos / Proteínas Proto-Oncogênicas B-raf / Melanoma Limite: Animals / Female / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2019 Tipo de documento: Article