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

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...

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Autores principales: Huang, Chung-Yu, Hsu, Li-Han, Chen, Chung-Yeh, Chang, Gee-Chen, Chang, Hui-Wen, Hung, Yi-Mei, Liu, Ko-Jiunn, Kao, Shu-Huei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017237/
https://www.ncbi.nlm.nih.gov/pubmed/31936895
http://dx.doi.org/10.3390/cancers12010181
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author Huang, Chung-Yu
Hsu, Li-Han
Chen, Chung-Yeh
Chang, Gee-Chen
Chang, Hui-Wen
Hung, Yi-Mei
Liu, Ko-Jiunn
Kao, Shu-Huei
author_facet Huang, Chung-Yu
Hsu, Li-Han
Chen, Chung-Yeh
Chang, Gee-Chen
Chang, Hui-Wen
Hung, Yi-Mei
Liu, Ko-Jiunn
Kao, Shu-Huei
author_sort Huang, Chung-Yu
collection PubMed
description 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.
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spelling pubmed-70172372020-02-28 Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy Huang, Chung-Yu Hsu, Li-Han Chen, Chung-Yeh Chang, Gee-Chen Chang, Hui-Wen Hung, Yi-Mei Liu, Ko-Jiunn Kao, Shu-Huei Cancers (Basel) Article 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. MDPI 2020-01-10 /pmc/articles/PMC7017237/ /pubmed/31936895 http://dx.doi.org/10.3390/cancers12010181 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Chung-Yu
Hsu, Li-Han
Chen, Chung-Yeh
Chang, Gee-Chen
Chang, Hui-Wen
Hung, Yi-Mei
Liu, Ko-Jiunn
Kao, Shu-Huei
Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy
title Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy
title_full Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy
title_fullStr Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy
title_full_unstemmed Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy
title_short Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy
title_sort inhibition of alternative cancer cell metabolism of egfr mutated non-small cell lung cancer serves as a potential therapeutic strategy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017237/
https://www.ncbi.nlm.nih.gov/pubmed/31936895
http://dx.doi.org/10.3390/cancers12010181
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