Activating MET kinase rearrangements in melanoma and Spitz tumours

作者：Yeh Iwei^*; Botton Thomas; Talevich Eric; Shain A Hunter; Sparatta Alyssa J; de la Fouchardiere Arnaud; Mully Thaddeus W; North Jeffrey P; Garrido Maria C; Gagnon Alexander; Vemula Swapna S; McCalmont Timothy H; LeBoit Philip E; Bastian Boris C

来源：Nature Communications, 2015, 6(1): 7174.

DOI：10.1038/ncomms8174

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 (PLC gamma 1) 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.

• 出版日期2015-5