Nishida Toshirou, Takahashi Tsuyoshi, Nishitani Akiko, Doi Toshihiko, Shirao Kuniaki, Komatsu Yoshito, Nakajima Kiyokazu, Hirota Seiichi
Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Int J Clin Oncol. 2009 Apr;14(2):143-9. doi: 10.1007/s10147-008-0822-y. Epub 2009 Apr 24.
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.
尽管苹果酸舒尼替尼已显示出对伊马替尼耐药的胃肠道间质瘤具有显著临床疗效，且患者耐受性可接受，预后有所改善，但该药物的耐药机制仍在研究中。
我们分析了17例伊马替尼耐药的胃肠道间质瘤患者中8例（7例男性，1例女性，中位年龄59岁）接受舒尼替尼治疗后的结果。舒尼替尼口服给药，起始剂量为37.5毫克/天、50毫克/天或75毫克/天，每日1次，服药4周，停药2周。
所有伊马替尼耐药以及舒尼替尼耐药的病灶均显示有存活的肿瘤细胞，这些细胞强烈重新表达KIT蛋白。伊马替尼治疗前的样本在第9外显子（n = 1）或第11外显子（n = 7）存在KIT基因异质性突变，7例伊马替尼耐药肿瘤在与原发突变相同的等位基因的ATP结合域或激活环中发生了二次突变。大多数在ATP结合域携带二次突变的伊马替尼耐药肿瘤患者从舒尼替尼治疗中获得了临床益处，而一些激活环发生突变的肿瘤则显示对该药物耐药。1例KIT基因第11和13外显子发生突变且对舒尼替尼部分缓解的肿瘤，在出现舒尼替尼耐药时，其激活环存在第三次突变。所有额外的二次和三次突变均位于与原发突变相同的等位基因上（顺式突变）。
这些发现表明，KIT基因激活环中的额外顺式突变可能是胃肠道间质瘤中舒尼替尼耐药的潜在原因。
