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Activating MET kinase rearrangements in melanoma and Spitz tumours

Author

Listed:
  • Iwei Yeh

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Thomas Botton

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Eric Talevich

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • A. Hunter Shain

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Alyssa J. Sparatta

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Arnaud de la Fouchardiere

    (Centre Léon Bérard)

  • Thaddeus W. Mully

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Jeffrey P. North

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Maria C. Garrido

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Alexander Gagnon

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Swapna S. Vemula

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Timothy H. McCalmont

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Philip E. LeBoit

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

  • Boris C. Bastian

    (and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California San Francisco)

Abstract

Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumours lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K) and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.

Suggested Citation

  • Iwei Yeh & Thomas Botton & Eric Talevich & A. Hunter Shain & Alyssa J. Sparatta & Arnaud de la Fouchardiere & Thaddeus W. Mully & Jeffrey P. North & Maria C. Garrido & Alexander Gagnon & Swapna S. Vem, 2015. "Activating MET kinase rearrangements in melanoma and Spitz tumours," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8174
    DOI: 10.1038/ncomms8174
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