Abstract 2092: Metabolic approach to EGFR-targeted therapy in non-small cell lung cancer

Abstract

Abstract Mutation of the epidermal growth factor receptor (EGFR) is a major genetic driver of non-small cell lung cancer (NSCLC). While first-line tyrosine-kinase inhibitors (TKIs) have improved patient survival, many patients eventually develop resistance to these drugs. Combination therapies are now being researched to overcome this resistance. Pathways that may synergize with EGFR signaling are of interest since a liability created with one compound may then be exploited by a second. It is well known that glycolysis is controlled by EGFR signaling in cancer cells. However, the interplay of cell metabolism and EGFR inhibitors is not fully understood. Using PC9 cells which have known constitutive EGFR activation, we examined the relative poise of ATP production from mitochondria and glycolysis. In response to any of four different TKIs: afatinib, CO-1686, dacomitinib and erlotinib, a rapid decrease in glycolytic activity was induced. However, the total ATP production rates were not changed significantly as a result of increased mitochondrial ATP production. We next examined the mitochondrial fuel sources which support this increase by selectively blocking individual fuel pathways. In the presence of either a mitochondrial pyruvate carrier or glutaminase inhibitor, total ATP production rate decreased, and cell viability followed. Taken together, these data suggest that a combinational application of EGFR-targeted therapy and mitochondrial-targeted therapy may provide metabolic stress to cancer cells. Further study is required to understand the interplay of the tumor microenvironment and metabolic niches that may be found therein. Citation Format: Yoonseok Kam, Pamela Swain, Natalia Romero, Brian P. Dranka. Metabolic approach to EGFR-targeted therapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2092.