Glucose metabolism-targeted therapy and withaferin A are effective for epidermal growth factor receptor tyrosine kinase inhibitor-induced drug-tolerant persisters.
Glucose metabolism-targeted therapy and withaferin A are effective for epidermal growth factor receptor tyrosine kinase inhibitor-induced drug-tolerant persisters.
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DOI：
10.1111/cas.13266
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发表时间：
2017-07
期刊：
影响因子：
5.7
通讯作者：
Nishimura Y
中科院分区：
文献类型：
--
作者：
Kunimasa K;Nagano T;Shimono Y;Dokuni R;Kiriu T;Tokunaga S;Tamura D;Yamamoto M;Tachihara M;Kobayashi K;Satouchi M;Nishimura Y
在通路靶向癌症药物治疗中，耐药持续存在者（DTP）的相对快速出现大大限制了整体治疗获益。然而，关于DTP在耐药性中的作用知之甚少。在这项研究中，我们研究了表皮生长因子受体酪氨酸激酶抑制剂诱导的DTP的特点，并探索了一种新的治疗策略，以克服这些DTP的出现。我们使用了两种EGFR突变的肺腺癌细胞系，PC 9和II-18。他们用2 μM吉非替尼治疗6、12或24天或6个月。我们通过定量RT-PCR分析了干细胞相关标志物的mRNA表达和细胞衰老相关蛋白的表达。然后根据CD 133的表达模式对DTP进行分选，并分析分选细胞的特征。最后，我们尝试通过葡萄糖代谢靶向治疗和干细胞样靶向药物withaferin A消融DTP。耐药持续细胞由至少两种类型的细胞组成，一种具有癌症干细胞样细胞（CSC）的特性，另一种具有治疗诱导衰老（TIS）细胞的特性。CD 133高细胞群具有CSC特性，而CD 133低细胞群具有TIS特性。含有TIS细胞的CD 133低细胞群显示出衰老相关的分泌表型，支持含有CSC的CD 133高细胞群的出现。葡萄糖代谢抑制剂有效地消除了CD 133 low细胞群。Withaferin A有效地消除了CD 133 high细胞群。根皮素和醉茄素A的组合有效抑制了吉非替尼耐药肿瘤的生长。
In pathway‐targeted cancer drug therapies, the relatively rapid emergence of drug‐tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of epidermal growth factor receptor–tyrosine kinase inhibitor‐induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR‐mutated lung adenocarcinoma cell lines, PC9 and II‐18. They were treated with 2 μM gefitinib for 6, 12, or 24 days or 6 months. We analyzed the mRNA expression of the stem cell‐related markers by quantitative RT‐PCR and the expression of the cellular senescence‐associated proteins. Then we sorted DTPs according to the expression pattern of CD133 and analyzed the features of sorted cells. Finally, we tried to ablate DTPs by glucose metabolism targeting therapies and a stem‐like cell targeting drug, withaferin A. Drug‐tolerant persisters were composed of at least two types of cells, one with the properties of cancer stem‐like cells (CSCs) and the other with the properties of therapy‐induced senescent (TIS) cells. The CD133high cell population had CSC properties and the CD133low cell population had TIS properties. The CD133low cell population containing TIS cells showed a senescence‐associated secretory phenotype that supported the emergence of the CD133high cell population containing CSCs. Glucose metabolism inhibitors effectively eliminated the CD133low cell population. Withaferin A effectively eliminated the CD133high cell population. The combination of phloretin and withaferin A effectively suppressed gefitinib‐resistant tumor growth.