Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

Sebastian Bender; Jan Gronych; Hans-Joerg Warnatz; Barbara Hutter; Susanne Groebner; Marina Ryzhova; Elke Pfaff; Volker Hovestadt; Florian Weinberg; Sebastian Halbach; Marcel Kool; Paul A. Northcott; Dominik Sturm; Lynn Bjerke; Thomas Zichner; Adrian M. Stutz; 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; Nathalene 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 Korbel; Sabine Schmidt; Stephan Wolf; Guido Reifenberger; Jorg 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; Int Canc Genome Consortium

doi:10.1038/nm.4204

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Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

Journal article

Peer reviewed

Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

Sebastian Bender, Jan Gronych, Hans-Joerg Warnatz, Barbara Hutter, Susanne Groebner, Marina Ryzhova, Elke Pfaff, Volker Hovestadt, Florian Weinberg, Sebastian Halbach, …

Nature medicine, Vol.22(11), pp.1314-1320

01/11/2016

DOI: https://doi.org/10.1038/nm.4204

PMID: 27748748

Abstract

Biochemistry & Molecular Biology

Cell Biology

Life Sciences & Biomedicine

Medicine, Research & Experimental

Research & Experimental Medicine

Science & Technology

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 similar to 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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Title: Recurrent MET fusion genes represent a drug target in pediatric glioblastoma
Creators - without role: Sebastian Bender - German Cancer Research Center
Jan Gronych - German Cancer Research Center
Hans-Joerg Warnatz - Max
Barbara Hutter - German Cancer Research Center
Susanne Groebner - Heidelberg
Marina Ryzhova - NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow, Russia
Elke Pfaff - German Cancer Research Center
Volker Hovestadt - German Cancer Research Center
Florian Weinberg - University of Freiburg
Sebastian Halbach - University of Freiburg
Marcel Kool - German Cancer Research Center
Paul A. Northcott - German Cancer Research Center
Dominik Sturm - German Cancer Research Center
Lynn Bjerke - Inst Canc Res, Div Mol Pathol, Sutton, Surrey, England
Thomas Zichner - Heidelberg
Adrian M. Stutz - Heidelberg
Kathrin Schramm - German Cancer Research Center
Bingding Huang - German Cancer Research Center
Ivo Buchhalter - German Cancer Research Center
Michael Heinold - German Cancer Research Center
Thomas Risch - Max Planck Society
Barbara C. Worst - German Cancer Research Center
Cornelis M. van Tilburg - German Cancer Research Center
Ursula D. Weber - German Cancer Research Center
Marc Zapatka - German Cancer Research Center
Benjamin Raeder - Heidelberg
David Milford - Heidelberg University
Sabine Heiland - Heidelberg University
Christof von Kalle - Heidelberg
Christopher Previti - German Cancer Research Center
Chris Lawerenz - German Cancer Research Center
Andreas E. Kulozik - Heidelberg University
Andreas Unterberg - Heidelberg University
Olaf Witt - Heidelberg
Andreas von Deimling - Heidelberg
David Capper - German Cancer Research Center
Nathalene Truffaux - University of Paris-Sud
Jacques Grill - University of Paris-Sud
Nada Jabado - McGill University
Astrid M. Sehested - University of Copenhagen
David Sumerauer - Charles University
Dorra Hmida-Ben Brahim - Farhat Hached Hosp, Dept Cytogenet & Reprod Biol, Sousse, Tunisia
Saoussen Trabelsi - Farhat Hached Hosp, Dept Cytogenet & Reprod Biol, Sousse, Tunisia
Ho-Keung Ng - Chinese University of Hong Kong
David Zagzag - New York University
Jeffrey C. Allen - New York University
Matthias A. Karajannis - New York University
Nicholas G. Gottardo - Princess Margaret Hosp Children, Dept Pediat Oncol & Haematol, Perth, WA, Australia
Chris Jones - Inst Canc Res, Div Mol Pathol, Sutton, Surrey, England
Jan Korbel - Heidelberg
Sabine Schmidt - Heidelberg
Stephan Wolf - Heidelberg
Guido Reifenberger - Heinrich Heine Univers Dusseldorf, Dept Neuropathol, Dusseldorf, Germany
Jorg Felsberg - Heinrich Heine Univers Dusseldorf, Dept Neuropathol, Dusseldorf, Germany
Benedikt Brors - Heidelberg
Christel Herold-Mende - Heidelberg
Hans Lehrach - Max
Tilman Brummer - University of Freiburg
Andrey Korshunov - Heidelberg
Roland Eils - Heidelberg
Marie-Laure Yaspo - Max
Stefan M. Pfister - Heidelberg
Peter Lichter - Heidelberg
David T. W. Jones - Heidelberg
Int Canc Genome Consortium
Publication Details: Nature medicine, Vol.22(11), pp.1314-1320
Publisher: Springer Nature
Number of pages: 7
Grant note: Dr. Mildred Scheel Foundation Scholarship P30CA016087 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 109252 / German Cancer Aid; Deutsche Krebshilfe UL 1 T12000038 / National Center for the Advancement of Translational Science (NCATS), US National Institutes of Health ICR German Cancer Consortium (DKTK, INFORM project) P30 CA16087 / Cancer Center Support Grant from the National Cancer Institute, US National Institutes of Health LA2983/2-1 / German Research Foundation (DFG) Making Headway Foundation 01KU1201A; 0315416C; 01GS0883; 031A425A; 01ZX1302 / German Federal Ministry of Education and Research (BMBF); Federal Ministry of Education & Research (BMBF) UL1TR000038 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) New York University Langone Human Specimen Resource Center, Laura and Isaac Perlmutter Cancer Center 16/193 / The Brain Tumour Charity Max Planck Society (Munich, Germany); Max Planck Society HA-305 / Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC) 11736 / Cancer Research UK NHS PedBrain Tumor Project 262055 / European Union (FP7); European Commission EDM Foundation Lemos Foundation German Cancer Research Center-Heidelberg Center for Personalized Oncology (DKFZ-HIPO)
Identifiers: 9919407108331
Academic Unit: Northern Borders University
Language: English
Resource Type: Journal article