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

Anna C Navis, Sanne A M van Lith, Sander M J van Duijnhoven, Maaike de Pooter, Bahar Yetkin-Arik, Pieter Wesseling, Wiljan J A J Hendriks, Hanka Venselaar, Marco Timmer, Patricia van Cleef, Paul van Bergen En Henegouwen, Myron G Best, Thomas D Wurdinger, Bastiaan B J Tops, William P J Leenders

Research output: Contribution to journalArticleAcademicpeer-review

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)131-44
Number of pages14
JournalActa Neuropathologica
Volume130
Issue number1
DOIs
Publication statusPublished - Jul 2015

Keywords

  • Anilides/pharmacology
  • Animals
  • Antibodies/metabolism
  • Carcinoma/genetics
  • Cell Line, Tumor
  • Female
  • Glioma/drug therapy
  • Hepatocyte Growth Factor/metabolism
  • Humans
  • Male
  • Mice
  • Neoplasm Grading
  • Neoplasm Transplantation
  • Prostatic Neoplasms, Castration-Resistant/genetics
  • Protein Conformation
  • Protein Kinase Inhibitors/pharmacology
  • Proto-Oncogene Proteins c-met/antagonists & inhibitors
  • Pyridines/pharmacology
  • RNA, Messenger/metabolism
  • Sarcoma/genetics
  • Sequence Deletion

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