Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene
Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene
复制标题
DOI：
10.1007/s10147-008-0822-y
复制
发表时间：
2009-04-01
影响因子：
3.3
通讯作者：
Hirota, Seiichi
中科院分区：
文献类型：
--
作者：
Nishida, Toshirou;Takahashi, Tsuyoshi;Hirota, Seiichi
虽然苹果酸苏尼替尼对耐伊马替尼的胃肠道间质瘤有显著的临床疗效，患者的耐受性可以接受，并改善了患者的预后，但耐药的机制仍在研究中。我们分析了17例接受舒尼替尼治疗的胃肠道间质瘤患者中的8例(7名男性和1名女性，中位年龄59岁)。开始剂量为37.5 mg/天、50 mg/天或75 mg/天，每天口服一次，疗程为4周和2周。所有伊马替尼和舒尼替尼耐药的皮损均显示存活的肿瘤细胞强烈重新表达KIT蛋白。伊马替尼前样本在外显子9(n=1)或外显子11(n=7)有不同的KIT突变，7例伊马替尼耐药肿瘤在与原始突变相同的等位基因中携带第二次突变，要么在ATP结合域，要么在激活环中。大多数携带ATP结合域次级突变的伊马替尼耐药肿瘤患者从舒尼替尼获得临床益处，而一些激活环突变的肿瘤显示出对该药物的耐药性。KIT基因第11外显子和第13外显子发生突变，并对舒尼替尼有部分反应的肿瘤，当显示对舒尼替尼耐药时，激活环中包含第三个突变。所有额外的次级和第三级突变与初级突变(顺式突变)位于同一个等位基因上。这些发现表明，KIT基因激活环中的一个额外顺式突变可能是胃肠道间质瘤对舒尼替尼耐药的潜在原因。
Although sunitinib malate has shown significant clinical effect on imatinib-resistant gastrointestinal stromal tumors, with acceptable tolerability and improved prognosis for the patients, the mechanism of resistance to the drug is still under investigation.We analyzed findings in 8 patients (seven men and one woman, median age, 59 years) out of 17 patients with imatinib-resistant gastrointestinal stromal tumors who had been treated with sunitinib. Sunitinib was orally administered once a day at a starting dose of 37.5 mg/day, 50 mg/day, or 75 mg/day, with 4 weeks on and 2 weeks off.All imatinib- as well as sunitinib-resistant lesions showed viable tumor cells strongly re-expressing the KIT protein. Pre-imatinib samples had heterogeneous KIT mutations either in exon 9 (n = 1) or exon 11 (n = 7), and seven imatinib-resistant tumors carried a secondary mutation either in the ATP-binding domain or in the activation loop in the same allele as the primary mutation. Most patients with imatinib-resistant tumors carrying secondary mutations in the ATP-binding domain obtained clinical benefits from sunitinib, whereas some tumors with mutations in the activation loop showed resistance to the drug. A tumor with mutations in exon 11 and 13 of the KIT gene, and showing partial response to sunitinib, harbored a third mutation in the activation loop when sunitinib resistance was shown. All additional secondary and tertiary mutations were located on the same allele as the primary mutation (cis-mutation).These findings indicate that an additional cis-mutation in the activation loop of the KIT gene could be a potential cause of sunitinib resistance in gastrointestinal stromal tumors.