Lung cancer cells with EGFR mutation and drug resistance develop altered bioenergetics patterns and become vulnerable to agents targeting mitochondria metabolic pathways   
 
Ko-Jiunn Liu^1,2, Yi-Mei Hung¹, Pei-Hua Wu¹, Shu-Huei Kao², Gee-Chen Chang ^3,4
1National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
²School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan
³Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
⁴Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
 
Cancer cells develop distinct bioenergetics machinery different from that observed in normal cells. Cancer cells consume large amounts of glucose that is used to produce ATP through a less efficient lactic acid metabolism pathway. Mitochondria activity is frequently suppressed in cancer cells to avoid the initiation of apoptosis. Due to these variations, targeting cellular bioenergetics pathways has become a new direction of cancer drug development in recent years. We have investigated the nature of a PE089 cell line, derived from a lung cancer patient with epidermal growth factor receptor (EGFR) exon 19 deletion, and an Ire sub-line derived after long-term exposure of PE089 in EGFR tyrosine kinase inhibitor (EGFR TKI). We found that during the development of EGFR TKI resistance, Ire cells acquired a secondary modulation on the bioenergetics pathway in that they switched from the dependence of glycolysis to mitochondria respiration pathway by substantially increasing the activity of mitochondria. However, together with this change in cellular bioenergetics, the Ire cells become more sensitive to intracellular reactive oxygen species (ROS) level and are more vulnerable to drugs targeting cellular bioenergetics such as metformin. Further studies revealed that the sensitivity of Ire cells to ROS can be rescued by providing glutathione or N-acetylcysteine, while the sensitivity to metformin can be reversed with sodium pyruvate. The Ire cells were more sensitive to 3-bromopyruvate than the PE089 cells in a MCT-1-dependent pathway. Several cell lines derived from patients treated with EGFR TKI also demonstrated similar characteristics as those of Ire cells. Our results suggest that targeting bioenergetics pathway may be an alternative therapy strategy for lung cancer with EGFR mutation and TKI resistance.