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Copper is required for oncogenic BRAF signalling and tumorigenesis.

Publication ,  Journal Article
Brady, DC; Crowe, MS; Turski, ML; Hobbs, GA; Yao, X; Chaikuad, A; Knapp, S; Xiao, K; Campbell, SL; Thiele, DJ; Counter, CM
Published in: Nature
May 22, 2014

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.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

May 22, 2014

Volume

509

Issue

7501

Start / End Page

492 / 496

Location

England

Related Subject Headings

  • Vemurafenib
  • Survival Analysis
  • Sulfonamides
  • Proto-Oncogene Proteins B-raf
  • Phosphorylation
  • Mitogen-Activated Protein Kinase Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 1
  • Mice
  • MAP Kinase Signaling System
 

Citation

APA
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ICMJE
MLA
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Brady, D. C., Crowe, M. S., Turski, M. L., Hobbs, G. A., Yao, X., Chaikuad, A., … Counter, C. M. (2014). Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature, 509(7501), 492–496. https://doi.org/10.1038/nature13180
Brady, Donita C., Matthew S. Crowe, Michelle L. Turski, G Aaron Hobbs, Xiaojie Yao, Apirat Chaikuad, Stefan Knapp, et al. “Copper is required for oncogenic BRAF signalling and tumorigenesis.Nature 509, no. 7501 (May 22, 2014): 492–96. https://doi.org/10.1038/nature13180.
Brady DC, Crowe MS, Turski ML, Hobbs GA, Yao X, Chaikuad A, et al. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature. 2014 May 22;509(7501):492–6.
Brady, Donita C., et al. “Copper is required for oncogenic BRAF signalling and tumorigenesis.Nature, vol. 509, no. 7501, May 2014, pp. 492–96. Pubmed, doi:10.1038/nature13180.
Brady DC, Crowe MS, Turski ML, Hobbs GA, Yao X, Chaikuad A, Knapp S, Xiao K, Campbell SL, Thiele DJ, Counter CM. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature. 2014 May 22;509(7501):492–496.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

May 22, 2014

Volume

509

Issue

7501

Start / End Page

492 / 496

Location

England

Related Subject Headings

  • Vemurafenib
  • Survival Analysis
  • Sulfonamides
  • Proto-Oncogene Proteins B-raf
  • Phosphorylation
  • Mitogen-Activated Protein Kinase Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 1
  • Mice
  • MAP Kinase Signaling System