Activating MET kinase rearrangements in melanoma and Spitz tumours

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. Vemula, Timothy H. McCalmont, Philip E. LeBoit and Boris C. Bastian ()
Additional contact information
Iwei Yeh: and 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
Eric Talevich: and 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
Alyssa J. Sparatta: and 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
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
Philip E. LeBoit: and 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

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8174

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