Information de reference pour ce titreAccession Number: | 00006056-201012160-00059.
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Author: | Johannessen, Cory M. 1,2,14; Boehm, Jesse S. 1,14; Kim, So Young 1,2,3,15; Thomas, Sapana R. 1,2; Wardwell, Leslie 2; Johnson, Laura A. 1,2; Emery, Caroline M. 2; Stransky, Nicolas 1; Cogdill, Alexandria P. 4; Barretina, Jordi 1,2,5; Caponigro, Giordano 6; Hieronymus, Haley 1,7,8; Murray, Ryan R. 3,9,10; Salehi-Ashtiani, Kourosh 3,9,10; Hill, David E. 3,9,10; Vidal, Marc 3,9,10; Zhao, Jean J. 9,11; Yang, Xiaoping 1; Alkan, Ozan 1; Kim, Sungjoon 12; Harris, Jennifer L. 12; Wilson, Christopher J. 6; Myer, Vic E. 6; Finan, Peter M. 6; Root, David E. 1; Roberts, Thomas M. 9; Golub, Todd 1,5,8; Flaherty, Keith T. 4; Dummer, Reinhard 13; Weber, Barbara L. 6; Sellers, William R. 6; Schlegel, Robert 6; Wargo, Jennifer A. 4; Hahn, William C. 1,2,3,5; Garraway, Levi A. 1,2,5,*
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Institution: | (1)Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA (2)Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA (3)Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA (4)Division of Surgical Oncology, Medical Oncology and Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA (5)Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA (6)Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (7)Current address: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA (8)Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA (9)Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA (10)Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA (11)Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA (12)Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA (13)Department of Dermatology, University Hospital of Zurich, Zurich CH-8091, Switzerland (14)These authors contributed equally to this work. (15)Present address: Duke Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina 27710, USA (S.Y.K).
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Title: | COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.[Letter]
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Source: | Nature. 468(7326):968-972, December 16, 2010.
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Abstract: | : Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas 1. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma 2 3 4 5 6-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials 7 8 9. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance 10 11 12. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies 13. Here we expressed ~600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
(C) 2010 Nature Publishing Group
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Language: | English.
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Document Type: | LETTER.
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Journal Subset: | Life & Biomedical Sciences. Science.
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ISSN: | 0028-0836
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NLM Journal Code: | 0410462, nsc
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DOI Number: | https://dx.doi.org/10.1038/natur...- ouverture dans une nouvelle fenêtre
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