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    Publication Date: 2014-04-11
    Description: The BRAF kinase is mutated, typically Val 600--〉Glu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers. BRAF(V600E) phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma, an effect that is increased when administered together with a BRAF(V600E) inhibitor. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAF(V600E)-driven signalling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 chimaera that phosphorylated ERK1/2 independently of Cu or an active ERK2 restored the tumour growth of murine cells lacking Ctr1. Cu chelators used in the treatment of Wilson disease decreased tumour growth of human or murine cells transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brady, Donita C -- Crowe, Matthew S -- Turski, Michelle L -- Hobbs, G Aaron -- Yao, Xiaojie -- Chaikuad, Apirat -- Knapp, Stefan -- Xiao, Kunhong -- Campbell, Sharon L -- Thiele, Dennis J -- Counter, Christopher M -- 092809/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- CA094184/CA/NCI NIH HHS/ -- CA172104/CA/NCI NIH HHS/ -- CA178145/CA/NCI NIH HHS/ -- DK074192/DK/NIDDK NIH HHS/ -- HL075443/HL/NHLBI NIH HHS/ -- K01 CA178145/CA/NCI NIH HHS/ -- P01 HL075443/HL/NHLBI NIH HHS/ -- P30 CA014236/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- R01 CA089614/CA/NCI NIH HHS/ -- R01 CA094184/CA/NCI NIH HHS/ -- R01 DK074192/DK/NIDDK NIH HHS/ -- R21 CA172104/CA/NCI NIH HHS/ -- T32 GM007184/GM/NIGMS NIH HHS/ -- T32 GM008570/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 May 22;509(7501):492-6. doi: 10.1038/nature13180. Epub 2014 Apr 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Nuffield Department of Clinical Medicine, Target Discovery Institute and Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. ; 1] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cation Transport Proteins/deficiency/genetics ; Cell Line, Tumor ; *Cell Transformation, Neoplastic/drug effects ; Chelating Agents/pharmacology/therapeutic use ; Copper/*metabolism/pharmacology ; Disease Models, Animal ; Drug Repositioning ; Drug Resistance, Neoplasm/drug effects ; Female ; Hepatolenticular Degeneration/drug therapy ; Humans ; Indoles/pharmacology ; Lung Neoplasms/drug therapy/genetics/metabolism/pathology ; *MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinase Kinases/antagonists & ; inhibitors/genetics/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics/*metabolism ; Sulfonamides/pharmacology ; Survival Analysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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