Letter | Published:

Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

Nature Medicine volume 22, pages 13141320 (2016) | Download Citation

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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Acknowledgements

For technical support and expertise, we thank A. Wittmann, L. Sieber, C. Xanthopoulos, D. Sohn and N. Mack, the DKFZ Genomics and Proteomics Core Facility, the DKFZ Center for Preclinical Research, R. Kabbe (Division of Theoretical Bioinformatics, DKFZ), M. Bieg and M. Schlesner (Division of Applied Bioinformatics, DKFZ), C. Jäger-Schmidt (Data Management Group, DKFZ), S. Rüffer and T. Giese from the Heidelberg University Hospital, M. Rabenstein from the NCT Heidelberg, S. Thamm, D. Balzereit, S. Dökel, M. Linser, A. Kovacsovics and V. Amstislavskiy from the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin, the tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg), and the Department of Oncogenomics (University of Amsterdam). Ntv-a; Cdkn2a−/−; Ptenfl/fl mice were kindly provided by E. Holland (Fred Hutchinson Cancer Research Center). This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants #01KU1201A, MedSys #0315416C, NGFNplus #01GS0883 and e:Med Joint Research Projects SYS-GLIO #031A425A and CancerTelSys #01ZX1302). Additional support came from the German Cancer Research Center–Heidelberg Center for Personalized Oncology (DKFZ-HIPO), the German Cancer Consortium (DKTK, INFORM project), the Max Planck Society (Munich, Germany), the European Union (FP7/2007-2013, grant ESGI #262055), the Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC, grant number HA-305), the German Research Foundation (DFG, grant LA2983/2-1), the EDM and the Lemos Foundations, the New York University Langone Human Specimen Resource Center, Laura and Isaac Perlmutter Cancer Center, supported in part by the Cancer Center Support Grant, P30 CA16087 from the National Cancer Institute, US National Institutes of Health, UL 1 TR000038 from the National Center for the Advancement of Translational Science (NCATS), US National Institutes of Health, and grants from the Making Headway Foundation. J. Gronych was supported by a Dr. Mildred Scheel Foundation Scholarship. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and the ICR as well as the project (Ministry of Health, Czech Republic) for conceptual development of research organization 00064203 (University Hospital Motol, Prague, Czech Republic).

Author information

Author notes

    • Stefan M Pfister
    • , Peter Lichter
    •  & David T W Jones

    These authors jointly directed this work.

    • Sebastian Bender
    • , Jan Gronych
    • , Hans-Jörg Warnatz
    •  & Barbara Hutter

    These authors contributed equally to this work.

Affiliations

  1. Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Sebastian Bender
    • , Susanne Gröbner
    • , Elke Pfaff
    • , Marcel Kool
    • , Paul A Northcott
    • , Dominik Sturm
    • , Barbara C Worst
    • , Stefan M Pfister
    •  & David T W Jones
  2. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.

    • Sebastian Bender
    • , Elke Pfaff
    • , Dominik Sturm
    • , Barbara C Worst
    • , Cornelis M van Tilburg
    • , Andreas E Kulozik
    • , Olaf Witt
    •  & Stefan M Pfister
  3. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Sebastian Bender
    • , Jan Gronych
    • , Susanne Gröbner
    • , Elke Pfaff
    • , Volker Hovestadt
    • , Marcel Kool
    • , Paul A Northcott
    • , Dominik Sturm
    • , Kathrin Schramm
    • , Barbara C Worst
    • , Cornelis M van Tilburg
    • , Ursula D Weber
    • , Marc Zapatka
    • , Andreas von Deimling
    • , David Capper
    • , Benedikt Brors
    • , Andrey Korshunov
    • , Stefan M Pfister
    • , Peter Lichter
    •  & David T W Jones
  4. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Jan Gronych
    • , Volker Hovestadt
    • , Kathrin Schramm
    • , Ursula D Weber
    • , Marc Zapatka
    •  & Peter Lichter
  5. Max Planck Institute for Molecular Genetics, Berlin, Germany.

    • Hans-Jörg Warnatz
    • , Thomas Risch
    • , Hans Lehrach
    •  & Marie-Laure Yaspo
  6. Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Barbara Hutter
    • , Ivo Buchhalter
    • , Michael Heinold
    •  & Benedikt Brors
  7. Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia.

    • Marina Ryzhova
  8. Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany.

    • Florian Weinberg
    • , Sebastian Halbach
    •  & Tilman Brummer
  9. Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany.

    • Florian Weinberg
    •  & Tilman Brummer
  10. Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, Sutton, UK.

    • Lynn Bjerke
    •  & Chris Jones
  11. European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.

    • Thomas Zichner
    • , Adrian M Stütz
    • , Benjamin Raeder
    •  & Jan O Korbel
  12. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Bingding Huang
    • , Ivo Buchhalter
    • , Chris Lawerenz
    •  & Roland Eils
  13. National Center for Tumor Diseases (NCT), Heidelberg, Germany.

    • Cornelis M van Tilburg
    •  & Benedikt Brors
  14. Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.

    • David Milford
    •  & Sabine Heiland
  15. Division of Translational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Christof von Kalle
  16. Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Christof von Kalle
    • , Christopher Previti
    • , Sabine Schmidt
    •  & Stephan Wolf
  17. Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.

    • Andreas Unterberg
    •  & Christel Herold-Mende
  18. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Olaf Witt
  19. Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.

    • Andreas von Deimling
    • , David Capper
    •  & Andrey Korshunov
  20. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Andreas von Deimling
    • , David Capper
    •  & Andrey Korshunov
  21. Unité Mixte de Recherche du Centre National de la Recherche Scientifique (CNRS) 8203, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Villejuif, France.

    • Nathalène Truffaux
    •  & Jacques Grill
  22. Department of Pediatric and Adolescent Oncology, Institut Gustave Roussy, Université Paris Sud, Villejuif, France.

    • Nathalène Truffaux
    •  & Jacques Grill
  23. Department of Pediatrics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec, Canada.

    • Nada Jabado
  24. Department of Human Genetics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec, Canada.

    • Nada Jabado
  25. Department of Pediatric Hematology and Oncology, Rigshospitalet, Copenhagen, Denmark.

    • Astrid M Sehested
  26. Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.

    • David Sumerauer
  27. Department of Cytogenetics and Reproductive Biology, Farhat Hached Hospital, Sousse, Tunisia.

    • Dorra Hmida-Ben Brahim
    •  & Saoussen Trabelsi
  28. Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China.

    • Ho-Keung Ng
  29. Department of Pathology, New York University School of Medicine, New York, USA.

    • David Zagzag
  30. Department of Neurosurgery, New York University School of Medicine, New York, USA.

    • David Zagzag
  31. Department of Pediatrics, New York University Langone Medical Center, New York, USA.

    • Jeffrey C Allen
    •  & Matthias A Karajannis
  32. Department of Pediatric Oncology and Haematology, Princess Margaret Hospital for Children, Perth, Western Australia, Australia.

    • Nicholas G Gottardo
  33. Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.

    • Nicholas G Gottardo
  34. School of Pediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.

    • Nicholas G Gottardo
  35. Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

    • Guido Reifenberger
    •  & Jörg Felsberg
  36. Comprehensive Cancer Center Freiburg CCCF, Medical Center – University of Freiburg, Freiburg, Germany.

    • Tilman Brummer
  37. Deutsches Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, Germany.

    • Tilman Brummer
  38. Institute for Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Heidelberg, Germany.

    • Roland Eils
  39. BioQuant Center, University of Heidelberg, Heidelberg, Germany.

    • Roland Eils

Consortia

  1. International Cancer Genome Consortium PedBrain Tumor Project

Authors

    Contributions

    S.B., J. Gronych, H.-J.W., E.P., F.W., S. Halbach, D. Sturm, L.B., A.M. Stütz, K.S., B.R., D.M., S. Heiland, C.v.K., S.S., S.W., J.F., T.B. performed and/or coordinated the experimental work. S.B., J. Gronych, H.-J.W., B. Hutter, S.G., V.H., M.K., P.A.N., T.Z., B. Huang, M.R., I.B., M.H., T.R., M.Z., C.P., C.L., B.C.W. performed data analysis. M.R., A.E.K., A.U., O.W., A.v.D., D.C., N.J., A.M. Sehested, D. Sumerauer, M.A.K., C.J., C.H.-M., A.K., J. Grill, N.T., C.M.v.T., B.C.W., D.H.-B.B., S.T., H.-K.N., D.Z., J.C.A., N.G.G. collected data and provided patient materials. S.B., J. Gronych, H.-J.W., B. Hutter, S.M.P., P.L. and D.T.W.J. prepared the initial manuscript and figures. S.B., J. Gronych, U.D.W., J.O.K., G.R., B.B., H.L., T.B., R.E., M.-L.Y., S.M.P., P.L. and D.T.W.J. provided project leadership.

    Competing interests

    The author declare no competing financial interests.

    Supplementary information

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    1. 1.

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      Supplementary Tables 1–5

    About this article

    Publication history

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    Accepted

    Published

    DOI

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

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