Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor
Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor
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DOI：
10.1200/jco.2003.04.190
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发表时间：
2003-12-01
影响因子：
45.3
通讯作者：
Fletcher, JA
中科院分区：
文献类型：
--
作者：
Heinrich, MC;Corless, CL;Fletcher, JA
目的：大多数胃肠道间质瘤（GIST）表达KIT或激酶血小板衍生生长因子受体α（PDGFRA）的组成型激活突变亚型，这些亚型是甲磺酸伊马替尼的潜在治疗靶点。在这些激酶和伊马替尼的临床反应突变之间的关系进行了检查，在一组患者与先进的GIST.Patients和方法：从127例患者纳入伊马替尼的II期临床研究的GISTs进行了检查突变的KIT或PDGFRA。结果：112例（88.2%）GIST中存在KIT激活突变，6例（4.7%）存在PDGFRA激活突变。大多数KIT突变涉及外显子9（n = 23）或外显子11（n = 85）。所有KIT突变亚型，但只有PDGFRA突变亚型的一个子集，在体外对伊马替尼敏感。携带外显子11 KIT突变的GIST患者的部分缓解率（PR）为83.5%，而携带外显子9 KIT突变或未检测到KIT或PDGFRA突变的患者的PR率为47.8%（P = 0.0006）和0.0%（P = 0.0001）。
Purpose: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST.Patients and Methods: GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome.Results: Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 1 1 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 1 1 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P =.0006) and 0.0% (P