Oncotarget

Research Papers:

Autophagy is required for crizotinib-induced apoptosis in MET-amplified gastric cancer cells

Rebecca D. Schroeder, Woonyoung Choi, David S. Hong and David J. McConkey _

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Oncotarget. 2017; 8:51675-51687. https://doi.org/10.18632/oncotarget.18386

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Abstract

Rebecca D. Schroeder1,3,4, Woonyoung Choi2, David S. Hong1,3,* and David J. McConkey2,3,4,*

1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

3The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA

4Experimental Therapeutics Academic Program, Houston, Texas, USA

*These authors have contributed equally to this work

Correspondence to:

David J. McConkey, email: djmcconkey@jhmi.edu

David S. Hong, email: dshong@mdanderson.org

Keywords: MET amplification, autophagy, resistance mechanism, gastric cancer

Received: January 29, 2016     Accepted: May 01, 2017     Published: June 07, 2017

ABSTRACT

MET amplification has been clinically credentialed as a therapeutic target in gastric cancer, but the molecular mechanisms underlying sensitivity and resistance to MET inhibitors are still not well understood. Using whole-genome mRNA expression profiling, we identified autophagy as a top molecular pathway that was activated by the MET inhibitor crizotinib in drug-sensitive human gastric cancer cells, and functional studies confirmed that crizotinib increased autophagy levels in the drug-sensitive cells in a concentration-dependent manner. We then used chemical and molecular approaches to inhibit autophagy in order to define its role in cell death. The clinically available inhibitor of autophagy, chloroquine, or RNAi-mediated knockdown of two obligate components of the autophagy pathway (ATG5 and ATG7) blocked cell death induced by crizotinib or RNAi-mediated knockdown of MET, and mechanistic studies localized the effects of autophagy to cytochrome c release from the mitochondria. Overall, the data reveal a novel relationship between autophagy and apoptosis in gastric cancer cells exposed to MET inhibitors. The observations suggest that autophagy inhibitors should not be used to enhance the effects of MET inhibitors in gastric cancer patients.


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