Abstract 55: Glucose supports EGFR-mutated lung adenocarcinoma survival by sustaining EGFR stability

Abstract

Abstract Tumor cells are genetically unstable, driven by genetic mutations that stimulate cancer cell proliferation and survival. These genetic mutations are generally linked to particular types of cancer. Oncogenic epidermal growth factor receptor (EGFR) is frequently mutated in non-small cell lung cancer (NSCLC), which is essential for NSCLC development and growth. However, the precise roles of EGFR in lung cancer metabolism are still unclear. Here we show that glucose (Glc) metabolism is critical for EGFR stability required for tumor growth and survival. EGFR mutation leads to a robust increase in Glc uptake, lactate production and glycolytic flux. Moreover, EGFR-mutated NSCLC cell lines are much more sensitive than EGFR WT to inhibition of Glc metabolism through EGFR degradation, suggesting that EGFR mutant NSCLCs rely more heavily than EFGR WT on aerobic glycolysis. Knockdown of EGFR in EGFR-mutated NSCLCs results in a decrease in expression level of genes that encode glycolysis enzymes, indicating that EGFR mutation leads to an increase in Glc metabolism and Glc dependence for growth and survival. Furthermore, inhibition of Glc metabolism shows a significant decrease in intracellular ATP, oxygen consumption and level of TCA cycle intermediates. Indeed, the addition of pyruvate dramatically rescues apoptotic cell death caused by EGFR degradation upon inhibition of Glc metabolism, suggesting that Glc to fuel the TCA cycle is essential for tumor survival. In addition, the inhibition of Glc metabolism overcomes T790M-mediated resistance to EGFR-TKIs. Together, our data suggest that the EGFR mutation mediates the reprogramming of Glc metabolism and this metabolic alteration represents an attractive target for new therapy of EGFR-mutated NSCLC. Citation Format: Jin Kyung Rho, Yun Jung Choi, Chang-Min Choi, Jae Cheol Lee. Glucose supports EGFR-mutated lung adenocarcinoma survival by sustaining EGFR stability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 55.