Inhibition of pyruvate dehydrogenase kinase 1 enhances the anti-cancer effect of EGFR tyrosine kinase inhibitors in non-small cell lung cancer.

Inhibition of pyruvate dehydrogenase kinase 1 enhances the anti-cancer effect of EGFR tyrosine kinase inhibitors in non-small cell lung cancer. Eur J Pharmacol. 2018 Sep 10;: Authors: Yang Z, Zhang S, Hu X, Tam KY Abstract 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...
Source: European Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharmacol Source Type: research