Recurrent MET fusion genes represent a drug target in pediatric glioblastoma.
Date
2016-11-01Author
International Cancer Genome Consortium PedBrain Tumor Project,
Type
Journal Article
Metadata
Show full item recordAbstract
Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.
Collections
Subject
International Cancer Genome Consortium PedBrain Tumor Project
Cell Line, Tumor
Animals
Humans
Mice
Mice, SCID
Glioblastoma
Brain Neoplasms
Anilides
Pyrazoles
Pyridines
Quinolines
Mitogen-Activated Protein Kinases
Proteins
Microtubule-Associated Proteins
Oncogene Proteins, Fusion
DNA, Neoplasm
RNA, Messenger
Protein Kinase Inhibitors
Xenograft Model Antitumor Assays
Sequence Analysis, DNA
Signal Transduction
Adolescent
Adult
Child
Child, Preschool
Infant
Female
Male
Proto-Oncogene Proteins c-met
Receptor-Like Protein Tyrosine Phosphatases, Class 5
Young Adult
Crizotinib
Research team
Glioma Team
Language
eng
Date accepted
2016-09-15
License start date
2016-11
Citation
Nature medicine, 2016, 22 (11), pp. 1314 - 1320
Publisher
NATURE PUBLISHING GROUP
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