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 tumors with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumors 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.
Highlights
Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy
Constitutive activation of signalling pathways controlling cell growth and proliferation by activating mutations in dominant oncogenes such BRAF, NRAS, KIT, GNAQ or GNA11 is found in the majority of melanocytic neoplasms[1,2,3,4,5]
Splice site mutations that result in exon 14 skipping, deletion within the juxtamembranous domain of MET, and increased MET activity have been identified in lung adenocarcinomas[30,31]
Summary
Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. 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. Constitutive activation of signalling pathways controlling cell growth and proliferation by activating mutations in dominant oncogenes such BRAF, NRAS, KIT, GNAQ or GNA11 is found in the majority of melanocytic neoplasms[1,2,3,4,5] These mutations tend to occur early during progression and are found in a mutually exclusive pattern in early-stage disease. MET fusions appear in a mutually exclusive pattern with previously identified melanoma oncogenes, are constitutively active and tumorigenic, and may serve as therapeutic targets for a subset of melanomas
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