Letter | Published:

Copper is required for oncogenic BRAF signalling and tumorigenesis

Nature volume 509, pages 492496 (22 May 2014) | Download Citation

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Abstract

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 cancers1,2. BRAFV600E 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 cancer3. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma4, an effect that is increased when administered together with a BRAFV600E inhibitor5. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu–MEK1 interaction6. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAFV600E-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 disease7 decreased tumour growth of human or murine cells transformed by BRAFV600E 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 BRAFV600E mutation.

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Acknowledgements

We thank M. McMahon, C. Cronin, E. Johnson, A. Stewart, D. S. Tyler and D. G. Kirsch for reagents, and C. Cronin, L. E. Crose, A. M. Jaeger, M. A. Luftig, E. Johnson, D. F. Kashatus, B. L. Lampson, J. P. Madigan, N. I. Nicely, Y. Nose, C. W. Pemble, N. L. K. Pershing, A. Stewart and J. D. Weyandt for technical support, discussions and/or review of the manuscript. This work was supported by National Institutes of Health grants CA178145 (D.C.B.), HL075443 (Proteomic Core K.X.), DK074192 (D.J.T.), CA094184 and CA172104 (C.M.C.), the Structural Genomics Consortium (Welcome Trust 092809/Z/10/Z), FP7 grant 278568 ‘PRIMES’ (S.K. and A.C.), the Stewart Trust (C.M.C.), the Edward Spiegel Fund of the Lymphoma Foundation (C.M.C.), and donations made in memory of Linda Woolfenden (C.M.C.).

Author information

Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Donita C. Brady
    • , Matthew S. Crowe
    • , Michelle L. Turski
    • , Dennis J. Thiele
    •  & Christopher M. Counter
  2. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • G. Aaron Hobbs
    •  & Sharon L. Campbell
  3. Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Xiaojie Yao
    •  & Kunhong Xiao
  4. Nuffield Department of Clinical Medicine, Target Discovery Institute and Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK

    • Apirat Chaikuad
    •  & Stefan Knapp
  5. Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Christopher M. Counter

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Contributions

Experiments were performed by D.C.B., M.S.C., M.L.T., G.A.H., X.Y. and K.X. All authors contributed to the study design. The manuscript was written by D.C.B. and C.M.C. with contributions by all authors.

Competing interests

A provisional patent application (D.C.B., M.L.T., D.J.T. and C.M.C.) has been filed regarding the use of Cu chelators for the treatment of BRAF and RAS mutation-positive cancers and a phase I melanoma trial investigating a copper chelator has been registered with clinicaltrials.gov (NCT02068079) with one of the authors serving as a co-investigator (C.M.C.).

Corresponding author

Correspondence to Christopher M. Counter.

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DOI

https://doi.org/10.1038/nature13180

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