Acetylsalicylic acid enhances antiproliferative effects of the EGFR inhibitor gefitinib in the absence of activating mutations in gastric cancer.
Acetylsalicylic acid enhances antiproliferative effects of the EGFR inhibitor gefitinib in the absence of activating mutations in gastric cancer.
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DOI：
10.3892/ijo.29.3.615
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发表时间：
2006-09
影响因子：
5.2
通讯作者：
J. C. Becker;C. Müller-Tidow;M. Stolte;T. Fujimori;N. Tidow;A. M. Ilea;C. Brandts;L. Tickenbrock;H. Serve;W. Berdel;W. Domschke;T. Pohle
中科院分区：
文献类型：
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作者：
J. C. Becker;C. Müller-Tidow;M. Stolte;T. Fujimori;N. Tidow;A. M. Ilea;C. Brandts;L. Tickenbrock;H. Serve;W. Berdel;W. Domschke;T. Pohle
表皮生长因子受体（EGFR）在胃癌中高度表达，表明其适合作为受体酪氨酸激酶（RTK）抑制剂的靶点。在本研究中，我们探讨了EGFR的作用及其作为胃癌治疗靶点的潜在用途。首先，我们分析了66例亚洲和白人胃癌患者的EGFR突变。没有发现激活EGFR突变，吉非替尼单独在胃癌细胞系中仅弱有效。然而，乙酰水杨酸（阿萨）显着增强吉非替尼的抑制作用，表明协同作用。全基因组表达谱分析表明，在胃腺癌细胞中，吉非替尼和阿萨共同给药的情况下，120个基因（32个诱导，88个抑制）受到显著调控。进一步的分析表明，几个重要的信号通路被有效地抑制同时暴露于吉非替尼和阿萨。我们的研究结果表明，虽然胃癌似乎并没有港口突变，使癌细胞组成性地对吉非替尼敏感，阿萨的共同管理可以加强RTK抑制剂活性的腺癌细胞通过EGFR激活。这是第一个有效调节癌症中EGFR抑制活性的报告。
The epidermal growth factor receptor (EGFR) is highly expressed in gastric cancer indicating its suitability as a target for receptor tyrosine kinase (RTK) inhibitors. In the current study we explored the role of EGFR and its potential use as a therapeutic target in gastric cancer. First we analyzed 66 gastric cancer samples of Asian and Caucasian patients for the presence of EGFR mutations. No activating EGFR mutations were found and gefitinib alone was only weakly effective in gastric cancer cell lines. However, acetylsalicylic acid (ASA) significantly enhanced the inhibitory effects of gefitinib indicating synergistic action. Whole genome expression profiling indicated significant regulation of 120 genes in the case of co-administration of gefitinib and ASA (32 induced, 88 repressed) in gastric adenocarcinoma cells. Further analyses indicated that several important signalling pathways were effectively inhibited by simultaneous exposure to gefitinib and ASA. Our findings indicate that although gastric cancer does not seem to harbour mutations which render the cancer cells constitutively susceptible to gefitinib, the co-administration of ASA can strengthen RTK inhibitor activity in adenocarcinoma cells by EGFR activation. This is the first report of effective modulation of EGFR-inhibition activity in cancer.