J Cancer 2017; 8(18):3774-3784. doi:10.7150/jca.21035

Research Paper

Combined Inhibitions of Glycolysis and AKT/autophagy Can Overcome Resistance to EGFR-targeted Therapy of Lung Cancer

Mingtong Ye1, 3, 4, Sufan Wang1, 3, Ting Wan1, 3, Rui Jiang1, 3, Yun Qiu1, 3, Lei Pei1, 3, Nengzhi Pang1, 3, Yuanling Huang1, 3, Yufeng Huang2, Zhenfeng Zhang2✉, Lili Yang1, 3✉

1. Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, PR China;
2. Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, PR China;
3. Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong, PR China;
4. The First Women and Children's Hospital of Huizhou, Huizhou, Guangdong, PR China.

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Ye M, Wang S, Wan T, Jiang R, Qiu Y, Pei L, Pang N, Huang Y, Huang Y, Zhang Z, Yang L. Combined Inhibitions of Glycolysis and AKT/autophagy Can Overcome Resistance to EGFR-targeted Therapy of Lung Cancer. J Cancer 2017; 8(18):3774-3784. doi:10.7150/jca.21035. Available from http://www.jcancer.org/v08p3774.htm

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Efficacy of EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, to treat human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR is not persistent due to drug resistance. Reprogramming in energy (especially glucose) metabolism plays an important role in development and progression of acquired resistance in cancer cells. We hypothesize that glucose metabolism in EGFR-TKI sensitive HCC827 cells and erlotinib-resistant sub-line of HCC827 (which we name it as erlotinib-resistant 6, ER6 cells in this study) is different and targeting glucose metabolism might be a treatment strategy for erlotinib-resistant NSCLCs. In this study, we found increased glucose uptakes, significant increase in glycolysis rate and overexpression of glucose transporter 1 in ER6 cells compared to its parental cells HCC827. We also found AKT and autophagy of ER6 cells were more activated than HCC827 cells after glucose starvation. Combining glucose deprivation and AKT or autophagy inhibitor could synergize and overcome the acquired resistance against EGFR-targeted therapy for NSCLCs. Our data suggest that the combinations of inhibitors of AKT or autophagy together with glucose deprivation could be novel treatment strategies for NSCLC with acquired resistance to targeted therapy.

Keywords: Drug resistance, glucose transporter 1, glycolysis, non-small cell lung cancers, autophagy, glucose deprivation.