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.
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For technical support and expertise, we thank A. Wittmann, L. Sieber, C. Xanthopoulos, D. Sohn and N. Mack, the DKFZ Genomics and Proteomics Core Facility, the DKFZ Center for Preclinical Research, R. Kabbe (Division of Theoretical Bioinformatics, DKFZ), M. Bieg and M. Schlesner (Division of Applied Bioinformatics, DKFZ), C. Jäger-Schmidt (Data Management Group, DKFZ), S. Rüffer and T. Giese from the Heidelberg University Hospital, M. Rabenstein from the NCT Heidelberg, S. Thamm, D. Balzereit, S. Dökel, M. Linser, A. Kovacsovics and V. Amstislavskiy from the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin, the tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg), and the Department of Oncogenomics (University of Amsterdam). Ntv-a; Cdkn2a−/−; Ptenfl/fl mice were kindly provided by E. Holland (Fred Hutchinson Cancer Research Center). This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants #01KU1201A, MedSys #0315416C, NGFNplus #01GS0883 and e:Med Joint Research Projects SYS-GLIO #031A425A and CancerTelSys #01ZX1302). Additional support came from the German Cancer Research Center–Heidelberg Center for Personalized Oncology (DKFZ-HIPO), the German Cancer Consortium (DKTK, INFORM project), the Max Planck Society (Munich, Germany), the European Union (FP7/2007-2013, grant ESGI #262055), the Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC, grant number HA-305), the German Research Foundation (DFG, grant LA2983/2-1), the EDM and the Lemos Foundations, the New York University Langone Human Specimen Resource Center, Laura and Isaac Perlmutter Cancer Center, supported in part by the Cancer Center Support Grant, P30 CA16087 from the National Cancer Institute, US National Institutes of Health, UL 1 TR000038 from the National Center for the Advancement of Translational Science (NCATS), US National Institutes of Health, and grants from the Making Headway Foundation. J. Gronych was supported by a Dr. Mildred Scheel Foundation Scholarship. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and the ICR as well as the project (Ministry of Health, Czech Republic) for conceptual development of research organization 00064203 (University Hospital Motol, Prague, Czech Republic).
Supplementary Tables 1–5