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Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired-resistance inevitably occurs after long-term exposure to the treatment of EGFR inhibitors. Glycolysis is a predominant process for most cancer cells to utilize glucose, which referred to as the Warburg Effect. Targeting critical enzymes, such as pyruvate dehydrogenase kinase 1 (PDK1) that inversely regulating the process of glycolysis could be a promising approach to work alone or in combination with other treatments for cancer therapy. The purpose of this study is to evaluate whether PDK1 inhibition could enhance the anti-cancer effects of EGFR-TKi. Herein, we utilized a recently reported PDK1 inhibitor 2,2-Dichloro-1-(4-isopropoxy-3-nitrophenyl)ethan-1-one (Cpd64), which was more potent and selective than dichloroacetate (DCA) and/or dichloroacetophenone (DAP), to study the mechanism of PDK1 inhibition in TKi-mediated anti-cancer activity. We found that the introduction of Cpd64 in EGFR-TKi therapy enhanced the anti-proliferative effects in EGFR-mutant NSCLC cells under hypoxia. In particular, Cpd64 was shown to increase the activity of pyruvate dehydrogenase (PDH) and improved XPHOS, such as elevated mitochondrial respiration, and increased ATP generation, which effectively modulated the upregulation of PDK1 by EGFR-TKi treatment. We have observed that Cpd64 effectively enhanced the tumor growth inhibition induced by erlotinib in a NCI-H1975 xenograft mouse model. Collectively, our results suggested that combined use of selective PDK inhibitor and EGFR-TKi could be a potential strategy for NSCLC therapy.