Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

Nat Med. 2016 Nov;22(11):1314-1320. doi: 10.1038/nm.4204. Epub 2016 Oct 17.

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.

MeSH terms

  • Adolescent
  • Adult
  • Anilides / pharmacology
  • Animals
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics*
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Crizotinib
  • DNA, Neoplasm
  • Female
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics*
  • Humans
  • Infant
  • Male
  • Mice
  • Mice, SCID
  • Microtubule-Associated Proteins / genetics
  • Mitogen-Activated Protein Kinases
  • Oncogene Proteins, Fusion / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proteins / genetics
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / genetics*
  • Pyrazoles / therapeutic use
  • Pyridines / therapeutic use
  • Quinolines / pharmacology
  • RNA, Messenger / metabolism*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / genetics
  • Sequence Analysis, DNA
  • Signal Transduction
  • Xenograft Model Antitumor Assays
  • Young Adult

Substances

  • 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