Journal Article

DKFZ-2017-01623

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Recurrent MET fusion genes represent a drug target in pediatric glioblastoma.

Bender, S. (First author)DKFZ* ; Gronych, J. ; Warnatz, H.-J. ; Hutter, B. (First author)DKFZ* ; Gröbner, S. ; Ryzhova, M. ; Pfaff, E.DKFZ* ; Hovestadt, V. ; Weinberg, F. ; Halbach, S. ; Kool, M.DKFZ* ; Northcott, P. A. ; Sturm, D. ; Bjerke, L. ; Zichner, T. ; Stütz, A. M. ; Schramm, K. ; Huang, B. ; Buchhalter, I.DKFZ* ; Heinold, M.DKFZ* ; Risch, T. ; Worst, B. C. ; van Tilburg, C. M. ; Weber, U. D. ; Zapatka, M.DKFZ* ; Raeder, B. ; Milford, D. ; Heiland, S. ; von Kalle, C.DKFZ* ; Previti, C. ; Lawerenz, C.DKFZ* ; Kulozik, A. E. ; Unterberg, A. ; Witt, O.DKFZ* ; von Deimling, A.DKFZ* ; Capper, D.DKFZ* ; Truffaux, N. ; Grill, J. ; Jabado, N. ; Sehested, A. M. ; Sumerauer, D. ; Brahim, D. H. ; Trabelsi, S. ; Ng, H.-K. ; Zagzag, D. ; Allen, J. C. ; Karajannis, M. A. ; Gottardo, N. G. ; Jones, C. ; Korbel, J. O. ; Schmidt, S.DKFZ* ; Wolf, S.DKFZ* ; Reifenberger, G. ; Felsberg, J. ; Brors, B.DKFZ* ; Herold-Mende, C. ; Lehrach, H. ; Brummer, T. ; Korshunov, A. ; Eils, R.DKFZ* ; Yaspo, M.-L. ; Pfister, S. (Last author)DKFZ* ; Lichter, P. (Last author)DKFZ* ; Jones, D. (Last author)DKFZ* ; , , International Cancer Genome Consortium PedBrain Tumor Project. (Collaboration author)

2016
Nature America Inc. New York, NY

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Please use a persistent id in citations: doi:10.1038/nm.4204

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.

Keyword(s): Anilides ; DNA, Neoplasm ; GSK 1363089 ; Microtubule-Associated Proteins ; Oncogene Proteins, Fusion ; Protein Kinase Inhibitors ; Proteins ; Pyrazoles ; Pyridines ; Quinolines ; RNA, Messenger ; TFG protein, human ; cytoplasmic linker protein 115 ; crizotinib ; Proto-Oncogene Proteins c-met ; Mitogen-Activated Protein Kinases ; PTPRZ1 protein, human ; Receptor-Like Protein Tyrosine Phosphatases, Class 5

Note: Bender S*, Gronych J*, Warnatz HJ*, Hutter B*(*shared first and senior authorships)Pfister SM*, Lichter P*, Jones DT*

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Contributing Institute(s):

1. Translationale Onkologie (G100)
2. Angewandte Bioinformatik (G200)
3. Pädiatrische Neuroonkologie (B062)
4. Molekulare Genetik (B060)
5. Geschäftsstelle (G010)
6. KKE Pädiatrische Onkologie (G340)
7. KKE Neuropathologie (G380)
8. Hochdurchsatz-Sequenzierung (W190)
9. Theoretische Bioinformatik (B080)
10. DKTK Heidelberg (L101)
11. DKTK Freiburg (L601)
12. DKTK Essen (L401)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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