Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein

Abstract MET has gained interest as a therapeutic target for a number of malignancies because of its involvement in tumorigenesis, invasion and metastasis. At present, a number of inhibitors, both antibodies against MET or its ligand hepatocyte growth factor, and small molecule MET tyrosine kinase inhibitors are in clinical trials. We here describe a novel variant of MET that is expressed in 6 % of high-grade gliomas. Characterization of this mutation in a glioma cell line revealed that it consists of an intronic deletion, resulting in a splice event connecting an intact splice donor site in exon 6 with the next splice acceptor site being that of exon 9. The encoded protein lacks parts of the extracellular IPT domains 1 and 2, encoded by exons 7 and 8, resulting in a novel pseudo-IPT and is named METΔ7−8. METΔ7−8 is located predominantly in the cytosol and is constitutively active. The auto-activating nature of METΔ7−8, in combination with a lack of transmembrane localization, renders METΔ7−8 not targetable using antibodies, although the protein is efficiently deactivated by MET-specific tyrosine kinase inhibitors. Testing of MET-expressing tumors for the presence of this variant may be important for treatment decision making.
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Publication date: Available online 17 October 2019Source: Cancer CellAuthor(s): Jamie N. Anastas, Barry M. Zee, Jay H. Kalin, Mirhee Kim, Robyn Guo, Sanda Alexandrescu, Mario Andres Blanco, Stefanie Giera, Shawn M. Gillespie, Jayanta Das, Muzhou Wu, Sarah Nocco, Dennis M. Bonal, Quang-De Nguyen, Mario L. Suva, Bradley E. Bernstein, Rhoda Alani, Todd R. Golub, Philip A. Cole, Mariella G. FilbinSummaryH3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysin...
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research
Purpose Gliomas constitute the most frequent primary brain tumors. Glioblastoma, the most common and malignant glioma in adults, has dismal prognosis with any current therapy. On the other hand, low-grade gliomas, the second most common type of gliomas, are potentially curative with appropriate treatment. Methods We conducted a meta-analysis to assess the performance of PET tracers with the best available evidence, namely, fluorodeoxyglucose (FDG), 11C-methionine (MET), and 18F-fluoroethyltyrosine (FET), in differentiating low- from high-grade gliomas. Results Twenty-three studies with a total of 994 participants w...
Source: Clinical Nuclear Medicine - Category: Nuclear Medicine Tags: Original Articles Source Type: research
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Conclusions: Our findings suggested that Dulcitol acted as a SIRT1 inhibitor, inducing apoptosis and inhibiting proliferation, migration and invasion of HepG2 cells and its modulatory mechanism seemed to be associated with regulation of MMPs, SIRT1/p53 pathways.Graphical abstractSchematic diagram of the proposed mechanisms of Dulcitol-induced apoptosis and anti-metastasis in hepatocellular carcinoma in vivo and in vitro.
Source: Phytomedicine - Category: Drugs & Pharmacology Source Type: research
Publication date: Available online 16 October 2019Source: Journal of Photochemistry and Photobiology B: BiologyAuthor(s): Deborah Piffaretti, Floriana Burgio, Marcus Thelen, Alain Kaelin-Lang, Paolo Paganetti, Michael Reinert, Maria Luisa D'AngeloAbstractFluorescence image guided surgical resection (FIGR) of high grade gliomas (HGGs) takes advantage of the accumulation of the tracer protoporphyrin IX (PpIX) in glioma cells following administration of 5-aminolevulinic acid (5-ALA). Occasionally, PpIX fluorescence intensity may be insufficient, thus compromising the efficacy and precision of the surgical intervention. The ca...
Source: Journal of Photochemistry and Photobiology B: Biology - Category: Speech-Language Pathology Source Type: research
Contributors : Chen-Xue Mao ; Zhao-Qian LiuSeries Type : Expression profiling by array ; Non-coding RNA profiling by arrayOrganism : Homo sapiensAstrocytoma is a common pathologic type of glioma, its survival and prognosis remain poor.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Non-coding RNA profiling by array Homo sapiens Source Type: research
No abstract available
Source: Neurology Today - Category: Neurology Tags: Disease Mechanisms Source Type: research
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Source: Nano Letters - Category: Nanotechnology Authors: Source Type: research
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Source: BMC Cancer - Category: Cancer & Oncology Authors: Tags: Research article Source Type: research
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Source: Journal of Neuro-Oncology - Category: Cancer & Oncology Source Type: research
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