Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors.
Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors.
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发表时间：
2003-08
影响因子：
5.7
通讯作者：
A. Frolov;S. Chahwan;M. Ochs;J. P. Arnoletti;Z. Pan;O. Favorova;J. Fletcher;M. von Mehren;B. Eisenberg;A. Godwin
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作者：
A. Frolov;S. Chahwan;M. Ochs;J. P. Arnoletti;Z. Pan;O. Favorova;J. Fletcher;M. von Mehren;B. Eisenberg;A. Godwin
胃肠道间质瘤(GIST)是最常见的胃肠道间充质恶性肿瘤。这一观察结果已成功地用于格列卫(也称为甲磺酸伊马替尼，STI-571)治疗无法切除和/或转移性胃肠道间质瘤患者的临床试验。格列卫的生物学机制以及其下游的分子效应通常尚不清楚。我们使用基于DNA微阵列的方法来确定GIST细胞中因格列卫的反应而改变的基因表达模式和信号通路。我们共鉴定出148个基因或表达序列标签(10,367个)是差异调控的；7个已知基因在治疗后显示出持久的反应。显著下调的基因有SPRY4A、FZD8、PDE2A、RTP801、FLJ20898和ARHGEF2。唯一上调的基因是MAFbx。在功能水平上，我们证明了伊马替尼抑制KIT、AKT和细胞外信号调节蛋白1/2的磷酸化，而不影响这些蛋白的总水平，并且这些反应基因的差异表达涉及丝裂原激活的蛋白激酶依赖和不依赖的通路的激活。为了试图将这些体外研究结果与临床数据相关联，我们根据CSTI571-B2222第二阶段试验，检查了服用格列卫前后患者的GIST针刺活检样本，证明评估的两个基因转录本的表达水平与临床反应很好地相关。本研究强调了体外细胞模型在体内研究伊马替尼对GIST反应的潜在价值，目的是确定临床反应的重要遗传标记、药物作用机制和可能的治疗靶点。
Gastrointestinal stromal tumors (GISTs), defined by the presence of constitutively activated KIT, are the most common gastrointestinal mesenchymal malignancies. This observation has been successfully exploited in clinical trials of Gleevec (also known as imatinib mesylate, STI-571) for patients with unresectable and/or metastatic GISTs. The biological mechanisms of Gleevec as well as its downstream molecular effects are generally unknown. We used a DNA microarray-based approach to identify gene expression patterns and signaling pathways that were altered in response to Gleevec in GIST cells. We identified a total of 148 genes or expressed sequence tags (of 10,367) that were differentially regulated; 7 known genes displayed a durable response after treatment. The significantly down-regulated genes were SPRY4A, FZD8, PDE2A, RTP801, FLJ20898, and ARHGEF2. The only up-regulated gene was MAFbx. On a functional level, we demonstrated that imatinib inhibited phosphorylation of KIT, AKT, and extracellular signal-regulated kinase 1/2 without affecting the total level of these proteins and that differential expression of these response genes involved activation of mitogen-activated protein kinase-dependent and -independent pathways. In an attempt to correlate these in vitro findings to clinical data, we examined GIST needle biopsy specimens taken from patients before and after Gleevec administration according to the CSTI571-B2222 Phase II trial and demonstrated that expression levels of the two gene transcripts evaluated correlated well with clinical response. This study emphasizes the potential value of an in vitro cell model to investigate GIST response to imatinib in vivo, for the purpose of identifying important genetic markers of clinical response, mechanisms of drug action, and possible therapeutic targets.