Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation
Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation
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DOI：
10.1158/1078-0432.ccr-04-2245
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发表时间：
2005-06-01
影响因子：
11.5
通讯作者：
DeMatteo, RP
中科院分区：
文献类型：
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作者：
Antonescu, CR;Besmer, P;DeMatteo, RP
大多数胃肠道间质瘤（GIST）在KIT或PDGFRA中有激活突变。伊马替尼是一种选择性酪氨酸激酶抑制剂，在约80%的转移性GIST患者中实现部分应答或疾病稳定。现在清楚的是，一些GIST患者在长期治疗期间对伊马替尼产生耐药性。为了确定耐药机制，我们研究了31例GIST患者，他们接受伊马替尼治疗，然后接受手术切除。有13名患者对伊马替尼无耐药，3名患者原发性耐药，15名患者在最初受益于该药物后获得性耐药。在非耐药组和原发耐药组中均未发现KIT或PDGFRA的继发性突变。相反，在15例获得性耐药患者中有7例（46%）发现继发性突变，其中每例患者在KIT外显子11中均存在原发性突变。大多数继发突变位于KIT外显子17。KIT磷酸化是异质性的，与伊马替尼的临床反应或突变状态无关。GIST中对伊马替尼的获得性耐药通常通过KIT激酶结构域中的继发性基因突变发生，这对延迟或预防伊马替尼耐药以及采用更新的靶向治疗的策略具有影响。
Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy. To identify the mechanism of resistance, we studied 31 patients with GIST who were treated with imatinib and then underwent surgical resection. There were 13 patients who were nonresistant to imatinib, 3 with primary resistance, and 15 with acquired resistance after initial benefit from the drug. There were no secondary mutations in KIT or PDGFRA in the nonresistant or primary resistance groups. In contrast, secondary mutations were found in 7 of 15 (46%) patients with acquired resistance, each of whom had a primary mutation in KIT exon 11. Most secondary mutations were located in KIT exon 17. KIT phosphorylation was heterogeneous and did not correlate with clinical response to imatinib or mutation status. That acquired resistance to imatinib in GIST commonly occurs via secondary gene mutation in the KIT kinase domain has implications for strategies to delay or prevent imatinib resistance and to employ newer targeted therapies.