Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis

Cancer Res. 2018 Jul 15;78(14):3995-4006. doi: 10.1158/0008-5472.CAN-17-1548. Epub 2018 Apr 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • China
  • Cytotoxins / pharmacology
  • Hep G2 Cells
  • Humans
  • Hypoxia / drug therapy*
  • Hypoxia / metabolism
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism*
  • Mice
  • Mice, Nude
  • Nuclear Proteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism*


  • Cell Cycle Proteins
  • Cytotoxins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Transcription Factors
  • YY1AP1 protein, human
  • Receptor, IGF Type 1