| Title |
Recurrent MET fusion genes represent a drug target in pediatric glioblastoma
|
|---|---|
| Published in |
Nature Medicine, October 2016
|
| DOI | 10.1038/nm.4204 |
| Pubmed ID | |
| 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 |
| Abstract |
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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X Demographics
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 12 | 22% |
| France | 4 | 7% |
| United Kingdom | 3 | 5% |
| Canada | 2 | 4% |
| India | 2 | 4% |
| Italy | 2 | 4% |
| New Zealand | 1 | 2% |
| Colombia | 1 | 2% |
| Greece | 1 | 2% |
| Other | 9 | 16% |
| Unknown | 18 | 33% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 33 | 60% |
| Scientists | 16 | 29% |
| Science communicators (journalists, bloggers, editors) | 5 | 9% |
| Practitioners (doctors, other healthcare professionals) | 1 | 2% |
Mendeley demographics
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 2 | <1% |
| Italy | 1 | <1% |
| Spain | 1 | <1% |
| Unknown | 199 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 35 | 17% |
| Student > Ph. D. Student | 33 | 16% |
| Student > Master | 17 | 8% |
| Student > Bachelor | 15 | 7% |
| Other | 14 | 7% |
| Other | 28 | 14% |
| Unknown | 61 | 30% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 45 | 22% |
| Medicine and Dentistry | 40 | 20% |
| Agricultural and Biological Sciences | 29 | 14% |
| Immunology and Microbiology | 5 | 2% |
| Neuroscience | 5 | 2% |
| Other | 14 | 7% |
| Unknown | 65 | 32% |