title: Recurrent MET fusion genes represent a drug target in pediatric glioblastoma.
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: D000293:Adolescent; D000328:Adult; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D000077547:Crizotinib; D004273:DNA, Neoplasm; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011506:Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult; D033921:Vesicular Transport Proteins
chemical_list: D000813:Anilides; D000077547:Crizotinib; D004273:DNA, Neoplasm; D008869:Microtubule-Associated Proteins; D020928:Mitogen-Activated Protein Kinases; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011506:Proteins; D019859:Proto-Oncogene Proteins c-met; D011720:Pyrazoles; D011725:Pyridines; D011804:Quinolines; D012333:RNA, Messenger; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; C544831:GSK 1363089; C096163:TFG protein, human; D033921:Vesicular Transport Proteins; C109878:cytoplasmic linker protein 115; C516895:PTPRZ1 protein, human