甲磺酸伊玛替尼靶向治疗胃肠道间质瘤的耐药机制研究  

Study on the mechanism of imatinib-induced resistantance in gastrointestinal stromal tumors

作　　者：周杨[1] 侯英勇[1] 谭云山[1] 卢韶华[1] 侯君[1] 刘景磊[1] 秦净[1] 沈坤堂[1] 孙益红[1] 

机构地区：[1]复旦大学附属中山医院病理科,上海200032

出　　处：《中华肿瘤杂志》2009年第8期597-601,共5页Chinese Journal of Oncology

基　　金：2003年国家自然科学基金青年基金项目（30300152）;2006年上海市科委科技攻关项目（064119622）

摘　　要：目的探讨甲磺酸伊玛替尼（IM）治疗胃肠道间质瘤（GIST）耐药的可能机制。方法收集8例临床确诊IM耐药的GIST患者耐药前（16例次）和耐药后（11例次）的组织标本，采用聚合酶链反应（PCR）和基因测序法检测c—kit基因第9、11、13和17号外显子以及PDGFRA基因第12和18号外显子序列，比较耐药前后基因的突变情况。结果8例耐药患者的肿瘤组织中，除原有基础基因改变外，均发现新突变，新突变集中在c-kit基因酪氨酸激酶结构域第13（2例）和第17号外显子（6例）上，其中第13号外显子均为654（V—A）突变，第17号外显子分别累及第816、820～823位点。结论c—kit基因酪氨酸激酶结构域继发突变是GIST患者经IM治疗后耐药的重要机制。Objective To investigate the mechanism of imafinib mesylate （IM） induced-resistantce in the patients with gastrointestinal stromal tumors （GISTs） and treated with imatinib. Methods Eight patients with GIST treated with IM developed secondary IM resistance. A total of 16 tumor samples （pre-IM therapy） and 11 tumor samples （post-IM treatment） were available. Exon 9, 11, 13, and 17 of c-kit gene as well as exon 12 and exon 18 of PDGFRA gene were sequenced. Results In addition to the changes of baseline genotype, the IM-induced gene changes were concentrated in the kinase domain of c-kit gene in all 8 patients, 2 of them were located in the exon 13 of c-kit gene presenting with V654A, while 6 in exon 17 involving 816 and 820 to 823 codons. Conclusion The mechanism of imatinib mesylate resistance after initial treatment with this agent in gastrointestinal stromal tumors is a novel mutation development in kinase domain of c-kit.

关 键 词：胃肠道间质瘤 甲磺酸伊玛替尼 C-KIT PDGFRA基因 

分 类 号：R686[医药卫生—骨科学]