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Enhancement of the anti-tumor activity of BIBW2992 by inhibition of glycolysis in non-small cell lung cancer harboring the EGFR T790M mutation

Title
 Enhancement of the anti-tumor activity of BIBW2992 by inhibition of glycolysis in non-small cell lung cancer harboring the EGFR T790M mutation 
Other Titles
 EGFR T790M 돌연변이를 지닌 비소세포폐암에서 당 대사의 저해를 통한 BIBW2992의 항종양 효능 증대 
Issue Date
2012
Publisher
 Graduate School, Yonsei University 
Description
Dept. of Medical Science/박사
Abstract
The secondary epidermal growth factor receptor (EGFR) T790M is the most common mechanism of resistance to reversible EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. Although BIBW2992 has been expected to overcome the resistance to reversible EGFR TKIs due to EGFR T790M mutation, it showed a limited efficacy in recent phase III clinical study. Increased glycolysis, a common feature of most cancer cells, has been considered as a potential target for treatment of cancer. In this study, it was found that the inhibition of glycolysis using 2-deoxy-D-glucose (2DG) improves the efficacy of BIBW2992 in H1975 and PC9-GR cells, the NSCLC cells with EGFR T790M. The combination treatment of 2DG and BIBW2992 induced intracellular ATP depletion in both H1975 and PC9-GR cells, resulting in activation of AMP-activated protein kinase (AMPK), the major energy-sensing kinase. The AMPK activation played a central role in the cytotoxicity by the combined treatment of 2DG and BIBW2992 through inhibition of mammalian target of rapamycin (mTOR). The alteration of AMPK/mTOR signaling pathway by the inhibition of glycolytic metabolism induced downregulation of Mcl-1, a member of anti-apoptotic Bcl-2 family which is critical for survival in H1975 and PC9-GR cells, by translational control. In in vivo xenograft study using PC9-GR cells, the combined treatment of 500 mg/kg 2DG and 5 mg/kg BIBW2992 showed more effective anti-tumor activity than the treatment of 2DG alone or BIBW2992 alone. In conclusion, this study examined whether glucose metabolism inhibition using 2DG enhances the sensitivity to BIBW2992 in NSCLC cells with EGFR T790M. Addition of 2DG increased the sensitivity to BIBW2992 accompanying apoptotic cell death in the cells. The cytotoxicity by the combination treatment of 2DG and BIBW2992 was mediated by Mcl-1 downregulation via alteration of AMPK/mTOR signaling pathway. These data suggest that the combined use of inhibitor of glycolytic metabolism and BIBW2992 is a potential therapeutic strategy for treatment of patients with acquired resistance to reversible EGFR TKIs due to secondary EGFR T790M.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/133702
Appears in Collections:
2. 학위논문 > 1. College of Medicine (의과대학) > 박사
Yonsei Authors
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