Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation.

Abstract

The MET receptor tyrosine kinase is deregulated primarily via overexpression or point mutations in various human cancers and different strategies for MET inhibition are currently evaluated in clinical trials. We observed by Western blot analysis and by Flow cytometry that MET inhibition by different MET small molecule inhibitors surprisingly increases in a dose-dependent manner total MET levels in treated cells. Mechanistically, this inhibition-related MET accumulation was associated with reduced Tyr1003 phosphorylation and MET physical association with the CBL ubiquitin ligase with concomitant decrease in MET ubiquitination. These data may suggest careful consideration for design of anti-MET clinical protocols.

• Authors: Dominic Leiser, Benoît Pochon, Wieslawa Blank-Liss, Paola Francica, Astrid A Glück, Daniel M Aebersold, Yitzhak Zimmer, Michaela Medová
• Journal: FEBS letters (FEBS Lett) Vol. 588 Issue 5 Pg. 653-8 (Mar 03 2014) ISSN: 1873-3468 [Electronic] England
• PMID: 24440350 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• ((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)
• 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
• EMD1214063
• Indoles
• Piperazines
• Pyrazoles
• Pyridazines
• Pyridines
• Pyrimidines
• Sulfonamides
• Sulfones
• Crizotinib
• Proto-Oncogene Proteins c-cbl
• MET protein, human
• Proto-Oncogene Proteins c-met
• CBL protein, human

Topics

• Animals
• Cell Line, Tumor
• Cell Membrane (drug effects, metabolism)
• Crizotinib
• Down-Regulation (drug effects)
• Humans
• Indoles (pharmacology)
• Lysosomes (metabolism)
• Mice
• Mutation, Missense
• NIH 3T3 Cells
• Piperazines (pharmacology)
• Proteolysis
• Proto-Oncogene Proteins c-cbl (metabolism)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics, metabolism)
• Pyrazoles (pharmacology)
• Pyridazines (pharmacology)
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Sulfonamides (pharmacology)
• Sulfones (pharmacology)
• Ubiquitination