gsk-1363089 and Brain-Neoplasms

Glioblastoma multiforme (GBM) is one of the most aggressive human cancers. The c-MET receptor tyrosine kinase (RTK) which is frequently deregulated in GBM is considered as a promising target for GBM treatment. The c-MET plays a key role in cell proliferation, cell cycle progression, invasion, angiogenesis, and metastasis. Here, we investigated the anti-tumour activity of foretinib, a c-MET inhibitor, on three human GBM cells (T98G, U87MG and U251).. Anti-proliferative effect of foretinib was determined using MTT, crystal violet staining, and clonogenic assays. PI and Annexin V/PI staining flow cytometry were used to evaluate the effects of foretinib on cell cycle and apoptosis, respectively. Scratch assay, qRT-PCR, western blot, and zymography analyses were applied to elucidate the molecular mechanisms underlying the anti-tumour activity of foretinib.. The results indicated that foretinib might have the therapeutic potential against human GBM which deserve further investigation.

Topics: Anilides; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Epithelial-Mesenchymal Transition; G2 Phase; Glioblastoma; Humans; Proto-Oncogene Proteins c-met; Quinolines; Receptors, Urokinase Plasminogen Activator; Signal Transduction

Topics: Amino Acid Substitution; Anilides; Animals; Benzamides; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Heterografts; Humans; Indazoles; Mice; Models, Molecular; Mutation; Oncogene Proteins, Fusion; Quinolines; Receptor, trkA; Structure-Activity Relationship

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.

Topics: Adolescent; Adult; Anilides; Animals; Brain Neoplasms; Cell Line, Tumor; Child; Child, Preschool; Crizotinib; DNA, Neoplasm; Female; Glioblastoma; Humans; Infant; Male; Mice; Mice, SCID; Microtubule-Associated Proteins; Mitogen-Activated Protein Kinases; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Proteins; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Quinolines; Receptor-Like Protein Tyrosine Phosphatases, Class 5; RNA, Messenger; Sequence Analysis, DNA; Signal Transduction; Xenograft Model Antitumor Assays; Young Adult