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    BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling.

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    Authors
    Sanchez-Laorden, Berta
    Viros, Amaya
    Girotti, Maria Romina
    Pedersen, M
    Saturno, Grazia
    Zambon, A
    Niculescu-Duvaz, D
    Turajlic, Samra
    Hayes, A
    Gore, Martin
    Larkin, J
    Lorigan, Paul C
    Cook, M
    Springer, C
    Marais, Richard
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    Affiliation
    Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX
    Issue Date
    2014-03-25
    
    Metadata
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    Abstract
    Melanoma is a highly metastatic and lethal form of skin cancer. The protein kinase BRAF is mutated in about 40% of melanomas, and BRAF inhibitors improve progression-free and overall survival in these patients. However, after a relatively short period of disease control, most patients develop resistance because of reactivation of the RAF-ERK (extracellular signal-regulated kinase) pathway, mediated in many cases by mutations in RAS. We found that BRAF inhibition induces invasion and metastasis in RAS mutant melanoma cells through a mechanism mediated by the reactivation of the MEK (mitogen-activated protein kinase kinase)-ERK pathway, increased expression and secretion of interleukin 8, and induction of protease-dependent invasion. These events were accompanied by a cell morphology switch from predominantly rounded to predominantly elongated cells. We also observed similar responses in BRAF inhibitor-resistant melanoma cells. These data show that BRAF inhibitors can induce melanoma cell invasion and metastasis in tumors that develop resistance to these drugs.
    Citation
    BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. 2014, 7 (318):ra30 Sci Signal
    Journal
    Science Signaling
    URI
    http://hdl.handle.net/10541/320636
    DOI
    10.1126/scisignal.2004815
    PubMed ID
    24667377
    Type
    Article
    Language
    en
    ISSN
    1937-9145
    ae974a485f413a2113503eed53cd6c53
    10.1126/scisignal.2004815
    Scopus Count
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