ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFRvIII, in the brain.
ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFRvIII, in the brain.
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DOI：
10.1158/1535-7163.mct-09-0953
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发表时间：
2010-04
影响因子：
5.7
通讯作者：
Cheng SY
中科院分区：
文献类型：
--
作者：
Yiin JJ;Hu B;Schornack PA;Sengar RS;Liu KW;Feng H;Lieberman FS;Chiou SH;Sarkaria JN;Wiener EC;Ma HI;Cheng SY
表皮生长因子受体（EGFR）vIII是一种突变的EGFR，经常在胶质母细胞瘤中过表达，并与受体酪氨酸激酶抑制剂的反应有关。在本研究中，我们研究了血管内皮生长因子受体2和EGFR双重抑制剂ZD 6474（ZACTIMA，凡德他尼）对表达EGFRvIII的胶质瘤生长和血管生成的影响。我们使用了两种胶质瘤异种移植模型，U87 MG细胞过度表达EGFRvIII和短期培养的原代胶质瘤GBM 8细胞与EGFRvIII。ZD 6474抑制肿瘤生长和血管生成，并诱导各种脑胶质瘤细胞凋亡。此外，与其对照相比，观察到表达EGFRvIII的U87 MG和GBM 8胶质瘤的显著抑制。使用表观扩散系数和三维T2* 加权测量值的磁共振成像分析验证了ZD 6474对表达EGFRvIII的GBM 8胶质瘤中肿瘤生长和血管生成的抑制作用。从机制上讲，ZD 6474通过减弱信号转导子和转录激活子3、Akt和Bcl-XL表达的活化磷酸化，对表达EGFRvIII的U87 MG/EGFRvIII、GBM 6和GBM 8细胞的细胞生长和存活的抑制作用优于未检出EGFRvIII的U87 MG或GBM 14细胞。尽管在较小程度上，ZD 6474也显示出对过表达野生型EGFR的U87 MG/EGFR和GBM 12细胞的抑制。此外，ZD 6474抑制两种细胞中细胞外信号调节激酶1/2的活化，组成型活性磷酸肌醇3-激酶的表达部分挽救了U87 MG/EGFRvIII细胞中ZD 6474的抑制作用。总之，这些数据表明，ZD 6474通过特异性阻断EGFRvIII激活的信号传导介质，显著抑制表达EGFRvIII的胶质瘤的生长和血管生成，表明ZD 6474在治疗过表达EGFRvIII的胶质母细胞瘤中的潜在应用。
Epidermal growth factor receptor (EGFR) vIII is a mutated EGFR that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors. In this study, we investigate the effect of ZD6474 (ZACTIMA, vandetanib), a dual inhibitor for vascular endothelial growth factor receptor 2 and EGFR on growth and angiogenesis of gliomas expressing EGFRvIII. We used two glioma xenograft models, U87MG cells overexpressing EGFRvIII and short-term cultured primary glioma GBM8 cells with EGFRvIII. ZD6474 inhibited tumor growth and angiogenesis and induced cell apoptosis in various brain gliomas. Moreover, significant inhibition of EGFRvIII-expressing U87MG and GBM8 gliomas was observed compared with their controls. Magnetic resonance imaging analysis using the apparent diffusion coefficient and three-dimensional T2*weighed measurements validated ZD6474 inhibition on tumor growth and angiogenesis in EGFRvIII-expressing GBM8 gliomas. Mechanistically, ZD6474 shows better inhibition of cell growth and survival of U87MG/EGFRvIII, GBM6, and GBM8 cells that express EGFRvIII than U87MG or GBM14 cells that have nondetectable EGFRvIII through attenuation of activated phosphorylation of signal transducer and activator of transcription 3, Akt, and Bcl-XL expression. Albeit in lesser extent, ZD6474 also displays suppressions of U87MG/EGFR and GBM12 cells that overexpress wild-type EGFR. Additionally, ZD6474 inhibits activation of extracellular signal-regulated kinase 1/2 in both types of cells, and expression of a constitutively active phosphoinositide 3-kinases partially rescued ZD6474 inhibition in U87MG/EGFRvIII cells. Taken together, these data show that ZD6474 significantly inhibited growth and angiogenesis of gliomas expressing EGFRvIII by specifically blocking EGFRvIII-activated signaling mediators, suggesting a potential application of ZD6474 in treatments for glioblastomas that overexpress EGFRvIII.