Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors.
Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors.
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DOI：
10.1016/j.yexcr.2014.04.012
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发表时间：
2014-08
影响因子：
3.7
通讯作者：
Masayuki Yasugi;N. Takigawa;N. Ochi;K. Ohashi;D. Harada;T. Ninomiya;T. Murakami;Y. Honda;E. Ichihara;M. Tanimoto;K. Kiura
中科院分区：
文献类型：
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作者：
Masayuki Yasugi;N. Takigawa;N. Ochi;K. Ohashi;D. Harada;T. Ninomiya;T. Murakami;Y. Honda;E. Ichihara;M. Tanimoto;K. Kiura
依维莫司是一种口服mTOR抑制剂。依维莫司对表皮生长因子受体（EGFR）突变肺癌的作用和作用机制尚不清楚。四吉非替尼敏感和耐药细胞系在本工作中使用。使用MTT测定法测定生长抑制。携带EGFR L 858 R突变的转基因小鼠在5至20周龄时用依维莫司（10 mg/kg/天）或单独的溶剂处理，然后处死。为了评价依维莫司在延长存活期方面的功效，从5周龄开始给予依维莫司（10 mg/kg/天）或媒介物。四种细胞系对依维莫司的敏感性相似。体外依维莫司处理后，磷酸化（p）mTOR和pS 6的表达受到抑制，而pAKT水平升高。依维莫司治疗组和对照组中长轴超过1 mm的肺肿瘤数量分别为1.9±0.9和9.4±3.2（t检验，p<0.001）。pS 6在依维莫司治疗期间被抑制。虽然依维莫司处理的EGFR转基因小鼠中未诱导细胞凋亡和自噬，但血管生成受到抑制。依维莫司治疗组的中位生存时间（58.0周）显著长于对照组（31.2周）（logrank检验，p<0.001）。这些结果表明，依维莫司通过抑制血管生成对肿瘤形成有间接作用，并且可能有效治疗由活化EGFR基因突变诱导的肺肿瘤。
Everolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10 mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10 mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimusin vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1 mm in the everolimus-treated and control groups were 1.9±0.9 and 9.4±3.2 (t-test,p<0.001), respectively. pS6 was suppressed during everolimus treatment. Although apoptosis and autophagy were not induced in everolimus-treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test,p<0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation.