Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma.
Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma.
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DOI：
10.1158/0008-5472.can-09-3965
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Teh BT
中科院分区：
文献类型：
--
作者：
Huang D;Ding Y;Zhou M;Rini BI;Petillo D;Qian CN;Kahnoski R;Futreal PA;Furge KA;Teh BT
广谱激酶抑制剂Sunitinib是治疗晚期肾透明细胞癌(CcRCC)的一线药物，ccRCC是一种致命的肾癌。不幸的是，大多数患者在大约一年的治疗后出现对舒尼替尼的耐药性和进展性疾病。在这项研究中，我们评估了对舒尼替尼的耐药机制，以确定克服它的潜在策略。异种移植模型的建立模拟了临床对舒尼替尼的耐药性。在对舒尼替尼耐药的肿瘤中发现了更高的微血管密度，这表明发生了对抗血管生成的逃避。值得注意的是，逃脱与肿瘤向血浆中分泌的白介素8(IL-8)增加以及联合应用IL-8中和抗体使肿瘤对舒尼替尼治疗重新敏感相一致。在对舒尼替尼治疗无效的患者中，IL-8在ccRCC肿瘤中的表达升高，支持IL-8水平可能预测对舒尼替尼的临床疗效的概念。我们的结果显示，IL-8是慢性肾细胞癌对舒尼替尼耐药的重要因素，也是逆转肾癌患者对舒尼替尼获得性或内在耐药性的候选治疗靶点。
The broad spectrum kinase inhibitor sunitinib is a first-line therapy for advanced clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Unfortunately, most patients develop sunitinib resistance and progressive disease after about 1 year of treatment. In this study, we evaluated the mechanisms of resistance to sunitinib to identify the potential tactics to overcome it. Xenograft models were generated that mimicked clinical resistance to sunitinib. Higher microvessel density was found in sunitinib-resistant tumors, indicating that an escape from antiangiogenesis occurred. Notably, escape coincided with increased secretion of interleukin-8 (IL-8) from tumors into the plasma, and coadministration of an IL-8 neutralizing antibody resensitized tumors to sunitinib treatment. In patients who were refractory to sunitinib treatment, IL-8 expression was elevated in ccRCC tumors, supporting the concept that IL-8 levels might predict clinical response to sunitinib. Our results reveal IL-8 as an important contributor to sunitinib resistance in ccRCC and a candidate therapeutic target to reverse acquired or intrinsic resistance to sunitinib in this malignancy.