Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models.
Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models.
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DOI：
10.1155/2014/638747
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发表时间：
2014
影响因子：
2.1
通讯作者：
Funahashi Y
中科院分区：
文献类型：
--
作者：
Tohyama O;Matsui J;Kodama K;Hata-Sugi N;Kimura T;Okamoto K;Minoshima Y;Iwata M;Funahashi Y
通过阻断血管内皮生长因子（VEGF）信号通路来抑制肿瘤血管生成是一种很有前途的甲状腺癌治疗策略。甲磺酸乐伐替尼（乐伐替尼）是VEGF受体（VEGFR 1 -3）和其他原癌和原癌受体酪氨酸激酶的强效抑制剂，包括成纤维细胞生长因子受体（FGFR 1 -4）、血小板衍生生长因子受体α（PDGFRα）、KIT和RET。我们检测了乐伐替尼对人甲状腺癌裸鼠移植瘤模型的抗肿瘤活性。口服乐伐替尼在5例分化型甲状腺癌（DTC）、5例未分化甲状腺癌（ATC）和1例甲状腺髓样癌（MTC）异种移植模型中显示出显著的抗肿瘤活性。乐伐替尼还对5种DTC和5种ATC异种移植物显示出抗血管生成活性，而乐伐替尼仅对11种甲状腺癌细胞系中的2种显示出体外抗增殖活性：即RO 82-W-1和TT细胞。蛋白质印迹分析显示，培养的RO 82-W-1细胞过表达FGFR 1，乐伐替尼可抑制FGFR 1及其下游效应子FRS 2的磷酸化。乐伐替尼还抑制TT细胞中RET与激活突变C634 W的磷酸化。这些数据表明，乐伐替尼主要通过抑制血管生成提供抗肿瘤活性，但也可在临床前人甲状腺癌模型中抑制FGFR和RET信号通路。
Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor (VEGF) signaling pathway is a promising therapeutic strategy for thyroid cancer. Lenvatinib mesilate (lenvatinib) is a potent inhibitor of VEGF receptors (VEGFR1–3) and other prooncogenic and prooncogenic receptor tyrosine kinases, including fibroblast growth factor receptors (FGFR1–4), platelet derived growth factor receptor α (PDGFRα), KIT, and RET. We examined the antitumor activity of lenvatinib against human thyroid cancer xenograft models in nude mice. Orally administered lenvatinib showed significant antitumor activity in 5 differentiated thyroid cancer (DTC), 5 anaplastic thyroid cancer (ATC), and 1 medullary thyroid cancer (MTC) xenograft models. Lenvatinib also showed antiangiogenesis activity against 5 DTC and 5 ATC xenografts, while lenvatinib showed in vitro antiproliferative activity against only 2 of 11 thyroid cancer cell lines: that is, RO82-W-1 and TT cells. Western blot analysis showed that cultured RO82-W-1 cells overexpressed FGFR1 and that lenvatinib inhibited the phosphorylation of FGFR1 and its downstream effector FRS2. Lenvatinib also inhibited the phosphorylation of RET with the activated mutation C634W in TT cells. These data demonstrate that lenvatinib provides antitumor activity mainly via angiogenesis inhibition but also inhibits FGFR and RET signaling pathway in preclinical human thyroid cancer models.