Antonescu Cristina R, Besmer Peter, Guo Tianhua, Arkun Knarik, Hom Glory, Koryotowski Beata, Leversha Margaret A, Jeffrey Philip D, Desantis Diann, Singer Samuel, Brennan Murray F, Maki Robert G, DeMatteo Ronald P
Department of Pathology, Sloan-Kettering Institute, New York, New York, USA.
Clin Cancer Res. 2005 Jun 1;11(11):4182-90. doi: 10.1158/1078-0432.CCR-04-2245.
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.
大多数胃肠道间质瘤（GIST）在KIT或血小板衍生生长因子受体α（PDGFRA）中存在激活突变。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患者中可实现部分缓解或疾病稳定。现在很清楚，一些GIST患者在长期治疗过程中会对伊马替尼产生耐药性。为了确定耐药机制，我们研究了31例接受伊马替尼治疗后接受手术切除的GIST患者。其中13例对伊马替尼不耐药，3例为原发性耐药，15例在最初从药物中获益后出现获得性耐药。在不耐药或原发性耐药组中，KIT或PDGFRA未发现二次突变。相比之下，在15例获得性耐药患者中有7例（46%）发现了二次突变，其中每例患者在KIT外显子11中都有一个原发性突变。大多数二次突变位于KIT外显子17。KIT磷酸化是异质性的，与对伊马替尼的临床反应或突变状态无关。GIST对伊马替尼的获得性耐药通常通过KIT激酶结构域中的二次基因突变发生，这对延迟或预防伊马替尼耐药以及采用更新的靶向治疗策略具有重要意义。
