Activating MET kinase rearrangements in melanoma and Spitz tumours

• DOI: 10.1038/ncomms8174
• Publication Date: 2015-05-27T14:04:59Z
• Authors: Iwei Yeh; Thomas Botton; Eric Talevich; A. Hunter Shain; Alyssa J. Sparatta; Arnaud de la Fouc...; Thaddeus W. Mully; Jeffrey P. North; Maria C. Garrido; Alexander Gagnon; Swapna S. Vemula; Timothy H. McCalmont; Philip E. LeBoit; Boris C. Bastian
• Keywords: Cabozantinib; Medullary Thyroid Cancer; Protein kinase domain; Targeted Therapy

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