Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model
Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model
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DOI：
10.1016/j.lungcan.2013.10.011
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发表时间：
2014-01-01
期刊：
影响因子：
5.3
通讯作者：
Kiura, Katsuyuki
中科院分区：
文献类型：
--
作者：
Murakami, Toshi;Takigawa, Nagio;Kiura, Katsuyuki
目的：STAT 3在诱导和维持促癌炎症微环境中起着至关重要的作用，并且据报道是EGFR突变的致癌作用的关键介质。STAT 3的激活是通过JAK家族激酶介导的。材料和方法：采用EGFR酪氨酸激酶受体（EGFR）19号外显子缺失突变的PC-9细胞株，建立了PC-9、PC-9/Van-R和PC-9/ER 3三种EGFR酪氨酸激酶受体（EGFR）耐药细胞系，观察JAK 1/2抑制剂AZD 1480对EGFR突变诱导的肺癌的作用。使用MIT测定法测量生长抑制。还在异种移植模型和EGFR转基因小鼠模型中评价了AZD 1480的作用。通过免疫印迹和免疫组织化学评估蛋白质表达。使用Student t检验比较组间差异。为了评价AZD 1480对存活率的功效，从转基因小鼠7周龄开始经口给予AZD 1480或溶剂。结果：耐药细胞和亲本细胞对AZD 1480的体外敏感性相似。AZD 1480（30或50 mg/kg/天，经口）减少了血管生成，并在小鼠异种移植模型中显示出显著的肿瘤消退：随后，转基因小鼠接受AZD 1480（30 mg/kg/天）或单独溶媒治疗。AZD 1480治疗组和对照组的肺肿瘤（长轴超过1 mm）数量分别为0.37 ± 0.18和2.25 ± 0.53（p
Objective: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation.Materials and methods: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MIT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method.Results: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model: Subsequently, the transgenic mice were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1 mm) in the AZD1480-treated group and control group were 0.37 +/- 0.18 and 2.25 +/- 0.53 (p