Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis
Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis
复制标题
多激酶抑制剂 CT-707 通过中断缺氧激活的 IGF-1R-YAP 轴来靶向肝癌
DOI：
10.1158/0008-5472.can-17-1548
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发表时间：
2018
期刊：
影响因子：
11.2
通讯作者：
Yang B
中科院分区：
文献类型：
--
作者：
Zhu Hong;Wang Dan-Dan;Yuan Tao;Yan Fang-Jie;Zeng Chen-Ming;Chen Zi-bo;Chen Ying;Zhou Tianyi;Fan Guang-Han;Ying Meidan;Cao Ji;Luo Peihua;He Qiaojun;Yang Bo;Dai Xiao-Yang;Liu Xi-Jie;Hu Yu;ong;Peng Yong;He QJ;Yang B
鉴于Yes相关蛋白（雅普）信号传导作为肝细胞癌（HCC）中缺氧癌细胞的关键存活输入，破坏雅普功能并维持缺氧是治疗HCC的有吸引力的方式。利用基于细胞的YAP-TEAD荧光素酶报告基因分析和功能分析，我们鉴定了CT-707，一种中国FDA批准的临床试验中的多激酶抑制剂，其对雅普功能具有显著的抑制活性。CT-707在缺氧条件下对肝癌细胞具有明显的细胞毒作用，其机制可能与抑制雅普信号通路有关。CT-707在HepG 2、Bel-7402和HCC患者来源的异种移植物中抑制肿瘤生长。从机制上讲，CT-707对雅普信号传导的抑制活性是由于缺氧激活的IGF 1 R的中断。总的来说，这些发现不仅鉴定CT-707作为有希望的针对HCC的低氧靶向剂，而且它们还揭示了IGF 1 R作为特异性调节低氧激活的雅普信号传导的新调节剂。©2018 AACR.
Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling.Significance:CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia.Cancer Res; 78(14); 3995–4006. ©2018 AACR.