Lim Ken-Hong, Huang Ming-Jer, Chen Li-Tzong, Wang Tsang-En, Liu Chien-Liang, Chang Cheng-Shyong, Liu Mei-Chin, Hsieh Reuy-Kuen, Tzen Chin-Yuan
Division of Hematology and Oncology, Mackay Memorial Hospital, 92, Section 2, Chungshan North Road, Taipei 10449, Taiwan.
Med Oncol. 2008;25(2):207-13. doi: 10.1007/s12032-007-9014-2. Epub 2007 Oct 6.
Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.
大多数胃肠道间质瘤（GISTs）与KIT或血小板衍生生长因子受体α（PDGFRA）基因的激活激酶突变相关，伊马替尼彻底改变了晚期GISTs的治疗方式。然而，大多数患者逐渐对伊马替尼产生耐药性。我们旨在鉴定伊马替尼耐药GISTs中的继发性激酶突变，并研究继发性激酶突变与伊马替尼临床反应之间的关系。本研究纳入了12例对伊马替尼产生耐药性的晚期GIST患者。对石蜡包埋的预处理GIST标本以及伊马替尼耐药后肿瘤的进展病灶进行分析，检测KIT基因外显子9、11、13和17以及PDGFRA基因外显子10、12、14和18中的激酶突变。除1例原发性肿瘤外，在所有原发性肿瘤中均发现了原发性KIT突变，其中1例存在新发的KIT外显子11双突变。在12例患者中，分别有7例和1例发现了KIT和PDGFRA的继发性激酶突变。2例患者在不同的进展部位存在不止一种继发性KIT突变，观察到了四种类型的克隆或多克隆进化。继发性PDGFRA外显子14突变H687Y是一种此前从未报道过的新突变。获得性继发性激酶突变是晚期GISTs继发性伊马替尼耐药的最重要原因。鉴定继发性激酶突变对于开发新的治疗策略具有重要意义。
