Combined Inhibitions of Glycolysis and AKT/autophagy Can Overcome Resistance to EGFR-targeted Therapy of Lung Cancer.
Combined Inhibitions of Glycolysis and AKT/autophagy Can Overcome Resistance to EGFR-targeted Therapy of Lung Cancer.
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糖酵解和 AKT/自噬的联合抑制可以克服肺癌对 EGFR 靶向治疗的耐药性
DOI：
10.7150/jca.21035
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发表时间：
2017
影响因子：
3.9
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Ye M;Wang S;Wan T;Jiang R;Qiu Y;Pei L;Pang N;Huang Y;Huang Y;Zhang Z;Yang L
EGFR靶向酪氨酸激酶抑制剂（TKI）（如厄洛替尼）治疗EGFR激活突变的人非小细胞肺癌（NSCLC）的疗效由于耐药性而不持久。能量（特别是葡萄糖）代谢的重编程在癌细胞获得性耐药的发展和进展中起着重要作用。我们假设EGFR-TKI敏感的HCC 827细胞和HCC 827的厄洛替尼耐药亚系（在本研究中我们将其命名为厄洛替尼耐药6，ER 6细胞）中的葡萄糖代谢是不同的，靶向葡萄糖代谢可能是厄洛替尼耐药NSCLC的治疗策略。在这项研究中，我们发现增加葡萄糖摄取，糖酵解速率显着增加和葡萄糖转运蛋白1在ER 6细胞中的过度表达相比，其亲本细胞HCC 827。另外，我们还发现ER 6细胞的AKT和自噬在葡萄糖饥饿后比HCC 827细胞更活跃。联合葡萄糖剥夺和AKT或自噬抑制剂可以协同并克服NSCLC对EGFR靶向治疗的获得性耐药性。我们的数据表明，AKT或自噬抑制剂与葡萄糖剥夺的组合可能是对靶向治疗产生获得性耐药的非小细胞肺癌的新型治疗策略。
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.
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影响因子：
2.5
作者：
Kim Y;Lin Q;Glazer PM;Yun Z
通讯作者：
Yun Z
影响因子：
158.5
作者：
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Hu, Yumin
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Flavahan, William A.;Wu, Qiulian;Hitomi, Masahiro;Rahim, Nasiha;Kim, Youngmi;Sloan, Andrew E.;Weil, Robert J.;Nakano, Ichiro;Sarkaria, Jann N.;Stringer, Brett W.;Day, Bryan W.;Li, Meizhang;Lathia, Justin D.;Rich, Jeremy N.;Hjelmeland, Anita B.
通讯作者：
Hjelmeland, Anita B.