Abstract 5408: Enhancement of the anti-tumor activity of afatinib by inhibition of glycolysis in non-small cell lung cancer harboring the EGFR T790M mutation .

Abstract

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 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, which are NSCLC cells with EGFR T790M. Treatment with a 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 inhibition of mammalian target of rapamycin (mTOR). The alteration of the AMPK/mTOR signaling pathway by inhibition of glucose metabolism induced specific downregulation of Mcl-1, a member of anti-apoptotic Bcl-2 family, through translational control. The enhancement of afatinib sensitivity by treatment of 2DG was confirmed in in vivo PC9-GR xenograft model. In conclusion, this study examined whether inhibition of glucose metabolism using 2DG enhances the sensitivity to afatinib in NSCLC cells with EGFR T790M through regulation of 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 treatment of patients with acquired resistance to reversible EGFR TKIs due to secondary EGFR T790M. Citation Format: Byoung Chul Cho, Hyun-Jung Kim, Sun Min Lim. Enhancement of the anti-tumor activity of afatinib by inhibition of glycolysis in non-small cell lung cancer harboring the EGFR T790M mutation . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5408. doi:10.1158/1538-7445.AM2013-5408 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.