Recurrent MET fusion genes represent a drug target in pediatric glioblastoma.
International Cancer Genome Consortium PedBrain Tumor Project
MetadataShow full item record
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.
Version of record
Cell Line, Tumor
Mitogen-Activated Protein Kinases
Oncogene Proteins, Fusion
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-met
Receptor-Like Protein Tyrosine Phosphatases, Class 5
Sequence Analysis, DNA
Xenograft Model Antitumor Assays
License start date
Nat Med, 22 (11), pp. 1314 - 1320
Showing items related by title, author, creator and subject.
Mardakheh, FK; Self, A; Marshall, CJDirectional cell migration involves reorientation of the secretory machinery. However, the molecular mechanisms that control this reorientation are not well characterised. Here, we identify a new Rho effector protein, named ...
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Mackay, A; Burford, A; Carvalho, D; Izquierdo, E; Fazal-Salom, J; Taylor, KR; Bjerke, L; Clarke, M; Vinci, M; Nandhabalan, M; Temelso, S; Popov, S; Molinari, V; Raman, P; Waanders, AJ; Han, HJ; Gupta, S; Marshall, L; Zacharoulis, S; Vaidya, S; Mandeville, HC; Bridges, LR; Martin, AJ; Al-Sarraj, S; Chandler, C; Ng, H-K; Li, X; Mu, K; Trabelsi, S; Brahim, DH-B; Kisljakov, AN; Konovalov, DM; Moore, AS; Carcaboso, AM; Sunol, M; de Torres, C; Cruz, O; Mora, J; Shats, LI; Stavale, JN; Bidinotto, LT; Reis, RM; Entz-Werle, N; Farrell, M; Cryan, J; Crimmins, D; Caird, J; Pears, J; Monje, M; Debily, M-A; Castel, D; Grill, J; Hawkins, C; Nikbakht, H; Jabado, N; Baker, SJ; Pfister, SM; Jones, DTW; Fouladi, M; von Bueren, AO; Baudis, M; Resnick, A; Jones, C (2017-10-09)We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating ...
RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses. Dolly, SO; Gurden, MD; Drosopoulos, K; Clarke, P; de Bono, J; Kaye, S; Workman, P; Linardopoulos, S (2017-09-26)BACKGROUND: F-box and WD40 repeat domain-containing 7 (FBXW7) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of multiple oncogenic substrates. The tumour suppressor function is frequently lost in ...