Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein
Navis, Anna C; van Lith, Sanne A M; van Duijnhoven, Sander M J; de Pooter, Maaike; Yetkin-Arik, Bahar; Wesseling, Pieter; Hendriks, Wiljan J A J; Venselaar, Hanka; Timmer, Marco; van Cleef, Patricia; van Bergen En Henegouwen, Paul; Best, Myron G; Wurdinger, Thomas D; Tops, Bastiaan B J; Leenders, William P J
(2015) Acta Neuropathologica, volume 130, issue 1, pp. 131 - 44
(Article)
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
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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 MET(Δ7-8). MET(Δ7-8) is located predominantly in the cytosol and is constitutively active. The auto-activating nature of MET(Δ7-8), in combination with a lack of transmembrane localization, renders MET(Δ7-8) 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.
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Keywords: Anilides, Animals, Antibodies, Carcinoma, Cell Line, Tumor, Female, Glioma, Hepatocyte Growth Factor, Humans, Male, Mice, Neoplasm Grading, Neoplasm Transplantation, Prostatic Neoplasms, Castration-Resistant, Protein Conformation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-met, Pyridines, RNA, Messenger, Sarcoma, Sequence Deletion, Journal Article, Research Support, Non-U.S. Gov't, Taverne
ISSN: 0001-6322
Publisher: Springer
(Peer reviewed)