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Activating MET Kinase Rearrangements in Melanoma and Spitz Tumors
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 activ...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446791/ https://www.ncbi.nlm.nih.gov/pubmed/26013381 http://dx.doi.org/10.1038/ncomms8174 |
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author | 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. |
author_facet | 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. |
author_sort | Yeh, Iwei |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4446791 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-44467912015-11-27 Activating MET Kinase Rearrangements in Melanoma and Spitz Tumors 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. Nat Commun Article 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. 2015-05-27 /pmc/articles/PMC4446791/ /pubmed/26013381 http://dx.doi.org/10.1038/ncomms8174 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article 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. Activating MET Kinase Rearrangements in Melanoma and Spitz Tumors |
title | Activating MET Kinase Rearrangements in Melanoma and Spitz Tumors |
title_full | Activating MET Kinase Rearrangements in Melanoma and Spitz Tumors |
title_fullStr | Activating MET Kinase Rearrangements in Melanoma and Spitz Tumors |
title_full_unstemmed | Activating MET Kinase Rearrangements in Melanoma and Spitz Tumors |
title_short | Activating MET Kinase Rearrangements in Melanoma and Spitz Tumors |
title_sort | activating met kinase rearrangements in melanoma and spitz tumors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446791/ https://www.ncbi.nlm.nih.gov/pubmed/26013381 http://dx.doi.org/10.1038/ncomms8174 |
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