title: 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 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.
authors: Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Anna C
authors: AC
authors: Navis
authors: Sanne A M
authors: SA
authors: van Lith
authors: Sander M J
authors: SM
authors: van Duijnhoven
authors: Maaike
authors: M
authors: de Pooter
authors: Bahar
authors: B
authors: Yetkin-Arik
authors: Pieter
authors: P
authors: Wesseling
authors: Wiljan J A J
authors: WJ
authors: Hendriks
authors: Hanka
authors: H
authors: Venselaar
authors: Marco
authors: M
authors: Timmer
authors: Patricia
authors: P
authors: van Cleef
authors: Paul
authors: P
authors: van Bergen En Henegouwen
authors: Myron G
authors: MG
authors: Best
authors: Thomas D
authors: TD
authors: Wurdinger
authors: Bastiaan B J
authors: BB
authors: Tops
authors: William P J
authors: WP
authors: Leenders
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D060787:Neoplasm Grading; D009368:Neoplasm Transplantation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion
chemical_list: D000813:Anilides; D000906:Antibodies; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; C558660:cabozantinib; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met