Comprehensive analysis of EGFR signaling pathways in Japanese patients with non-small cell lung cancer
Comprehensive analysis of EGFR signaling pathways in Japanese patients with non-small cell lung cancer
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DOI：
10.1016/j.lungcan.2009.01.005
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发表时间：
2009-10-01
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：
Hosokawa, Shinobu;Toyooka, Shinichi;Kiura, Katsuyuki
目的：将基础研究成果转化到肿瘤实践中是必要的。EGFR突变与EGFR信号通路组分之间的分子关联在实验室实验中得到了广泛的研究，尽管仍存在争议。此外，EGFR下游信号传导对非小细胞肺癌（NSCLC）患者临床特征的影响仍未确定。患者和方法：共招募了93例手术切除的非小细胞肺癌患者。采用直接序列法分析EGFR突变状态。免疫组化法检测EGFR、磷酸化EGFR （pEGFR）、磷酸化Akt （pAkt）、磷酸化MAPK （pMAPK）蛋白表达水平。结果：37例（40%）患者的肿瘤中存在EGFR突变（18外显子1,22外显子，19外显子和21外显子14）。61例（66%）、27例（29%）检测到EGFR、pEGFR、pAkt和pMAPK的蛋白表达。58例（62%），41例（44%）。pAkt的表达与女性性别和不吸烟史显著相关，在EGFR突变的肿瘤中经常上调（p < 0.05）。EGFR磷酸化与EGFR蛋白表达密切相关（p < 0.05），但与EGFR突变无关。在患者生存方面，所有分子生物标志物均不能预测手术切除后的生存，但pMAPK表达可预测吉非替尼术后复发患者治疗后的不良预后（p < 0.05），提示吉非替尼治疗后pMAPK表达与患者生存获益有很强的相关性。结论：本研究结果可为非小细胞肺癌患者使用吉非替尼治疗MAP激酶信号通路提供新的见解。2009爱思唯尔爱尔兰有限公司版权所有。
Purpose: Translational approach is essentially needed to return the achievement of basic researches to oncological practice. The molecular associations among EGFR mutation and the components of EGFR signaling pathways have been extensively studied in laboratory experiments, although were still controversial. Moreover, the impact of downstream signaling of EGFR on clinical features in patients with non-small cell lung cancer (NSCLC) remains undetermined.Patients and methods: A total of 93 surgically resected NSCLC patients were recruited the study. EGFR mutation status was analyzed by direct sequence method. The protein expression levels of EGFR, phosphorylated EGFR (pEGFR), phosphorylated Akt (pAkt), and phosphorylated MAPK (pMAPK) were determined by immunohistochemistry.Results: There were 37 (40%) patients whose tumor harboring EGFR mutations (1 in exon 18 22 in exon, 19, and 14 in exon 21). Protein expression of EGFR, pEGFR, pAkt, and pMAPK was detected in 61 (66%), 27 (29%). 58 (62%), and 41 (44%) patients, respectively. The expression of pAkt was significantly associated with female gender and never-smoking history, and it was frequently upregulated in tumors harboring EGFR mutations (p < 0.05, each). Phosphorylation of EGFR was closely correlated with the EGFR protein expression (p < 0.05), but not with the EGFR mutations. In regard to patient survival, none of the molecular biomarkers was predictive for survival after surgical resection, but pMAPK expression was predictive for poor prognosis after gefitinib treatment in patients with postoperative recurrence (p < 0.05), suggesting the strong linkage between pMAPK expression and survival benefit from gefitinib.Conclusion: Our result could provide new insight into MAP kinase signaling when we treat NSCLC patients with gefitinib. (C) 2009 Elsevier Ireland Ltd. All rights reserved.