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Glycolysis Inhibition Sensitizes Non–Small Cell Lung Cancer with T790M Mutation to Irreversible EGFR Inhibitors via Translational Suppression of Mcl-1 by AMPK Activation

Authors
 Sun Mi Kim  ;  Mi Ran Yun  ;  Yun Kyoung Hong  ;  Flavio Solca  ;  Joo-Hang Kim  ;  Hyun-Jung Kim  ;  Byoung Chul Cho 
Citation
 MOLECULAR CANCER THERAPEUTICS, Vol.12(10) : 2145-2156, 2013 
Journal Title
 MOLECULAR CANCER THERAPEUTICS 
ISSN
 1535-7163 
Issue Date
2013
MeSH
AMP-Activated Protein Kinases/genetics* ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Deoxyglucose/administration & dosage ; Drug Resistance, Neoplasm ; Glycolysis/genetics ; Humans ; Mutation ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Protein Biosynthesis/drug effects ; Protein Kinase Inhibitors/administration & dosage ; Quinazolines/administration & dosage* ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/genetics* ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/genetics
Keywords
EGFR T790M ; NSCLC ; 2DG ; afatinib ; AMPK/mTOR/Mcl-1
Abstract
The secondary EGF receptor (EGFR) T790M is the most common mechanism of resistance to reversible EGFR-tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. Although afatinib (BIBW2992), a second-generation irreversible EGFR-TKI, was expected to overcome the acquired resistance, it showed limited efficacy in a recent phase III clinical study. In this study, we found that the inhibition of glycolysis using 2-deoxy-d-glucose (2DG) improves the efficacy of afatinib in H1975 and PC9-GR NSCLC cells with EGFR T790M. Treatment with the combination of 2DG and afatinib induced intracellular ATP depletion in both H1975 and PC9-GR cells, resulting in activation of AMP-activated protein kinase (AMPK). AMPK activation played a central role in the cytotoxicity of the combined treatment with 2DG and afatinib through the inhibition of mTOR. The alteration of the AMPK/mTOR signaling pathway by the inhibition of glucose metabolism induced specific downregulation of Mcl-1, a member of the antiapoptotic Bcl-2 family, through translational control. The enhancement of afatinib sensitivity by 2DG was confirmed in the in vivo PC9-GR xenograft model. In conclusion, this study examined whether the inhibition of glucose metabolism using 2DG enhances sensitivity to afatinib in NSCLC cells with EGFR T790M through the regulation of the AMPK/mTOR/Mcl-1 signaling pathway. These data suggest that the combined use of an inhibitor of glucose metabolism and afatinib is a potential therapeutic strategy for the treatment of patients with acquired resistance to reversible EGFR-TKIs due to secondary EGFR T790M.
Full Text
http://mct.aacrjournals.org/content/12/10/2145.long
DOI
10.1158/1535-7163.MCT-12-1188
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Sun Mi(김선미)
Kim, Joo Hang(김주항)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/88759
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