Publication Date:
2016-11-09
Description:
Nature Medicine 22, 1314 (2016). doi:10.1038/nm.4204 Authors: Sebastian Bender, Jan Gronych, Hans-Jörg Warnatz, Barbara Hutter, Susanne Gröbner, Marina Ryzhova, Elke Pfaff, Volker Hovestadt, Florian Weinberg, Sebastian Halbach, Marcel Kool, Paul A Northcott, Dominik Sturm, Lynn Bjerke, Thomas Zichner, Adrian M Stütz, Kathrin Schramm, Bingding Huang, Ivo Buchhalter, Michael Heinold, Thomas Risch, Barbara C Worst, Cornelis M van Tilburg, Ursula D Weber, Marc Zapatka, Benjamin Raeder, David Milford, Sabine Heiland, Christof von Kalle, Christopher Previti, Chris Lawerenz, Andreas E Kulozik, Andreas Unterberg, Olaf Witt, Andreas von Deimling, David Capper, Nathalène Truffaux, Jacques Grill, Nada Jabado, Astrid M Sehested, David Sumerauer, Dorra Hmida-Ben Brahim, Saoussen Trabelsi, Ho-Keung Ng, David Zagzag, Jeffrey C Allen, Matthias A Karajannis, Nicholas G Gottardo, Chris Jones, Jan O Korbel, Sabine Schmidt, Stephan Wolf, Guido Reifenberger, Jörg Felsberg, Benedikt Brors, Christel Herold-Mende, Hans Lehrach, Tilman Brummer, Andrey Korshunov, Roland Eils, Marie-Laure Yaspo, Stefan M Pfister, Peter Lichter & David T W Jones 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.
Print ISSN:
1078-8956
Electronic ISSN:
1546-170X
Topics:
Biology
,
Medicine
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