Multikinase Inhibitor Ct-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated Igf-1r-Yap Axis

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  • 作者:Zhu, H., Wang, D. D., Yuan, T., Yan, F. J., Zeng, C. M., Dai, X. Y., Chen, Z. B., Chen, Y., Zhou, T., Fan, G. H., Ying, M., Cao, J., Luo, P., Liu, X. J., Hu, Y., Peng, Y., He, Q. & Yang, B.
  • 期刊:Cancer research 78, 3995-4006 (2018)
  • 阅读原文

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.

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