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Experimental and Molecular Therapeutics

Abstract 1909: Cytoprotective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells

Magali Humbert, Michaela Medová, Daniel M. Aebersold, Mario P. Tschan and Yitzhak Zimmer
Magali Humbert
1Experimental Oncology/Hematology, Department of Clinical Research, University of Bern, Bern, Switzerland
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Michaela Medová
2Radiation Oncology, Department of Clinical Research, University of Bern, Bern, Switzerland
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Daniel M. Aebersold
2Radiation Oncology, Department of Clinical Research, University of Bern, Bern, Switzerland
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Mario P. Tschan
1Experimental Oncology/Hematology, Department of Clinical Research, University of Bern, Bern, Switzerland
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Yitzhak Zimmer
2Radiation Oncology, Department of Clinical Research, University of Bern, Bern, Switzerland
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DOI: 10.1158/1538-7445.AM2012-1909 Published April 2012
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Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

Abstract

MET, also known as hepatocyte growth factor receptor, is a receptor tyrosine kinase (RTK) that plays an important role both in normal cellular function as well as in oncogenesis. In many different 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. Although promising results have been obtained with a variety of different MET RTK inhibitors, different resistance mechanisms were found. We hypothesized that autophagy, a self-digesting recycling mechanism for cellular organelles and macromolecules with cytoprotective functions, might be involved in resistance towards MET inhibitors. Autophagy induced upon MET inhibition might support cancer cell survival. We therefore aimed at investigating the involvement of autophagy upon MET inhibition in GTL-16 gastric adenocarcinoma cells. First, we treated GTL-16 cells with the MET inhibitor PHA665752. We observed a marked induction of autophagy in these cells upon MET inhibition as measured by LC3I/LC3II conversion and GFP-LC3 dot formation. Similar results were seen in another gastric adenocarcinoma cell line, namely MKN-45. Next, to investigate if MET inhibition-mediated induction of autophagy is a protective mechanism, we treated GTL-16 cells with PHA665752 in combination with compounds that influence autophagic activity. Interestingly, a combination treatment of MET and autophagy inhibitors (3-Methyladenine, 3-MA) significantly (MWU, p<0.001) decreased cell viability as determined by an MTT assay. In contrast, using the autophagy activator lithium chloride in combination with MET inhibitors, cell viability was significantly increased (p<0.01). All data were confirmed using a second MET-inhibitor. To exclude that 3-MA autophagy independent functions account for the increased cell death during treatment with PHA665752, we inhibited autophagy by knocking down the key autophagy gene ATG7 in GTL-16 cells using lentiviral vectors expression small hairpin (sh)RNA targeting ATG7. These “autophagy knockdown” GTL-16 cells displayed a significant increase in cell death upon MET inhibition as compared to GTL-16 control cells expressing a scrambled control shRNA. In conclusion, our results point to a cytoprotective function of autophagy in response to MET inhibition. The use of MET in combination with autophagy inhibitors may represent a novel therapeutic option for the treatment of gastric carcinoma with aberrant MET activity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1909. doi:1538-7445.AM2012-1909

  • ©2012 American Association for Cancer Research
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Cancer Research: 72 (8 Supplement)
April 2012
Volume 72, Issue 8 Supplement
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Abstract 1909: Cytoprotective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells
Magali Humbert, Michaela Medová, Daniel M. Aebersold, Mario P. Tschan and Yitzhak Zimmer
Cancer Res April 15 2012 (72) (8 Supplement) 1909; DOI: 10.1158/1538-7445.AM2012-1909

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Abstract 1909: Cytoprotective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells
Magali Humbert, Michaela Medová, Daniel M. Aebersold, Mario P. Tschan and Yitzhak Zimmer
Cancer Res April 15 2012 (72) (8 Supplement) 1909; DOI: 10.1158/1538-7445.AM2012-1909
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Cancer Research Online ISSN: 1538-7445
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