Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells.

Abstract

MET, also known as hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase with an important role, both in normal cellular function as well as in oncogenesis. In many cancer types, abnormal activation of MET is related to poor prognosis and various strategies to inhibit its function, including small molecule inhibitors, are currently in preclinical and clinical evaluation. Autophagy, a self-digesting recycling mechanism with cytoprotective functions, is induced by cellular stress. This process is also induced upon cytotoxic drug treatment of cancer cells and partially allows these cells to escape cell death. Thus, since autophagy protects different tumor cells from chemotherapy-induced cell death, current clinical trials aim at combining autophagy inhibitors with different cancer treatments. We found that in a gastric adenocarcinoma cell line GTL-16, where MET activity is deregulated due to receptor overexpression, two different MET inhibitors PHA665752 and EMD1214063 lead to cell death paralleled by the induction of autophagy. A combined treatment of MET inhibitors together with the autophagy inhibitor 3-MA or genetically impairing autophagy by knocking down the key autophagy gene ATG7 further decreased cell viability of gastric cancer cells. In general, we observed the induction of cytoprotective autophagy in MET expressing cells upon MET inhibition and a combination of MET and autophagy inhibition resulted in significantly decreased cell viability in gastric cancer cells.

• Authors: Magali Humbert, Michaela Medová, Daniel M Aebersold, Andree Blaukat, Friedhelm Bladt, Martin F Fey, Yitzhak Zimmer, Mario P Tschan
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 431 Issue 2 Pg. 264-9 (Feb 08 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 23313490 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• 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
• Protein Kinase Inhibitors
• Pyridazines
• Pyrimidines
• Sulfones
• 3-methyladenine
• MET protein, human
• Proto-Oncogene Proteins c-met
• Atg7 protein, human
• Autophagy-Related Protein 7
• Ubiquitin-Activating Enzymes
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Adenocarcinoma (enzymology)
• Autophagy (drug effects, genetics)
• Autophagy-Related Protein 7
• Cell Line, Tumor
• Cell Survival
• Drug Resistance, Neoplasm
• Gene Knockdown Techniques
• Humans
• Indoles (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors)
• Pyridazines (pharmacology)
• Pyrimidines (pharmacology)
• Stomach Neoplasms (enzymology)
• Sulfones (pharmacology)
• Ubiquitin-Activating Enzymes (genetics)