Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

S. Bender, J. Gronych, H.J. Warnatz, B. Hutter, S. Gröbner, M. Ryzhova, E. Pfaff, V. Hovestadt, F. Weinberg, S. Halbach, M. Kool, P.A. Northcott, D. Sturm, L. Bjerke, T. Zichner, A.M. Stütz, K. Schramm, B. Huang, I. Buchhalter, M. Heinold & 40 others T. Risch, B.C. Worst, C.M. Van Tilburg, U.D. Weber, M. Zapatka, B. Raeder, D. Milford, S. Heiland, C. Von Kalle, C. Previti, C. Lawerenz, A.E. Kulozik, A. Unterberg, O. Witt, A. Von Deimling, D. Capper, N. Truffaux, J. Grill, N. Jabado, A.M. Sehested, D. Sumerauer, D.H.B. Brahim, S. Trabelsi, H.K. Ng, D. Zagzag, J.C. Allen, M.A. Karajannis, Nicholas Gottardo, C. Jones, J.O. Korbel, S. Schmidt, S. Wolf, G. Reifenberger, J. Felsberg, B. Brors, C. Herold-Mende, H. Lehrach, T. Brummer, A. Korshunov, R. Eils

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Abstract

© 2016 Nature America, Inc., part of Springer Nature. All rights reserved.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.
Original languageEnglish
Pages (from-to)1314-1320
JournalNature Medicine
Volume22
Issue number11
DOIs
Publication statusPublished - 2016

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Bender, S., Gronych, J., Warnatz, H. J., Hutter, B., Gröbner, S., Ryzhova, M., ... Eils, R. (2016). Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nature Medicine, 22(11), 1314-1320. https://doi.org/10.1038/nm.4204