Copper is required for oncogenic BRAF signalling and tumorigenesis.
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.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Donita C
DC
Brady
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Matthew S
MS
Crowe
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Michelle L
ML
Turski
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
G Aaron
GA
Hobbs
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Xiaojie
X
Yao
Nuffield Department of Clinical Medicine, Target Discovery Institute and Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
Apirat
A
Chaikuad
Nuffield Department of Clinical Medicine, Target Discovery Institute and Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
Stefan
S
Knapp
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kunhong
K
Xiao
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Sharon L
SL
Campbell
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Dennis J
DJ
Thiele
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.
Christopher M
CM
Counter
D000818:Animals; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D000079923:Copper Transporter 1; D004195:Disease Models, Animal; D058492:Drug Repositioning; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006527:Hepatolenticular Degeneration / Q000188:drug therapy; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D016019:Survival Analysis; D000077484:Vemurafenib
D027682:Cation Transport Proteins; D002614:Chelating Agents; D000079923:Copper Transporter 1; D007211:Indoles; C490077:Slc31a1 protein, mouse; D013449:Sulfonamides; D000077484:Vemurafenib; D003300:Copper; D048493:Proto-Oncogene Proteins B-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases