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Predictors of Outcomes in Patients with EGFR-Mutated Non-Small Cell Lung Cancer Receiving EGFR Tyrosine Kinase Inhibitors: A Systematic Review and Meta-Analysis
Open AccessArticle

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy

by Chung-Yu Huang 1,2, Li-Han Hsu 1,3,4, Chung-Yeh Chen 2, Gee-Chen Chang 4,5,6, Hui-Wen Chang 1,2,7, Yi-Mei Hung 8, Ko-Jiunn Liu 2,8,9,† and Shu-Huei Kao 1,2,7,*,†
1
Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
2
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
3
Division of Pulmonary and Critical Care Medicine, Sun Yat-Sen Cancer Center, Taipei 11259, Taiwan
4
Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan
5
Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan
6
Institute of Biomedical Sciences, National Chung-Hsing University, Taichung 40227, Taiwan
7
Department of Medical Laboratory, Taipei Medical University Hospital, Taipei 11031, Taiwan
8
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli 35035, Taiwan
9
Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan 70101, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this study.
Cancers 2020, 12(1), 181; https://doi.org/10.3390/cancers12010181
Received: 6 November 2019 / Revised: 8 January 2020 / Accepted: 8 January 2020 / Published: 10 January 2020
Targeted therapy is an efficient treatment for patients with epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Therapeutic resistance invariably occurs in NSCLC patients. Many studies have focused on drug resistance mechanisms, but only a few have addressed the metabolic flexibility in drug-resistant NSCLC. In the present study, we found that during the developing resistance to tyrosine kinase inhibitor (TKI), TKI-resistant NSCLC cells acquired metabolic flexibility in that they switched from dependence on glycolysis to oxidative phosphorylation by substantially increasing the activity of the mitochondria. Concurrently, we found the predominant expression of monocarboxylate transporter 1 (MCT-1) in the TKI-resistant NSCLC cells was strongly increased in those cells that oxidized lactate. Thus, we hypothesized that inhibiting MCT-1 could represent a novel treatment strategy. We treated cells with the MCT-1 inhibitor AZD3965. We found a significant decrease in cell proliferation and cell motility in TKI-sensitive and TKI-resistant cells. Taken together, these results demonstrated that gefitinib-resistant NSCLC cells harbored higher mitochondrial bioenergetics and MCT-1 expression. These results implied that targeting mitochondrial oxidative phosphorylation proteins or MCT-1 could serve as potential treatments for both TKI-sensitive and –resistant non-small cell lung cancer. View Full-Text
Keywords: NSCLC; gefitinib-resistant; EGFR; alternative metabolism; monocarboxylate transporter 1 NSCLC; gefitinib-resistant; EGFR; alternative metabolism; monocarboxylate transporter 1
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Huang, C.-Y.; Hsu, L.-H.; Chen, C.-Y.; Chang, G.-C.; Chang, H.-W.; Hung, Y.-M.; Liu, K.-J.; Kao, S.-H. Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy. Cancers 2020, 12, 181.

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