1. Academic Validation
  2. CT-707, a Novel FAK Inhibitor, Synergizes with Cabozantinib to Suppress Hepatocellular Carcinoma by Blocking Cabozantinib-Induced FAK Activation

CT-707, a Novel FAK Inhibitor, Synergizes with Cabozantinib to Suppress Hepatocellular Carcinoma by Blocking Cabozantinib-Induced FAK Activation

  • Mol Cancer Ther. 2016 Dec;15(12):2916-2925. doi: 10.1158/1535-7163.MCT-16-0282.
Dan-Dan Wang 1 Ying Chen 1 Zi-Bo Chen 1 Fang-Jie Yan 1 Xiao-Yang Dai 1 Mei-Dan Ying 1 Ji Cao 1 Jian Ma 1 Pei-Hua Luo 1 Yong-Xin Han 2 Yong Peng 3 Ying-Hui Sun 3 Hui Zhang 3 Qiao-Jun He 1 Bo Yang 1 Hong Zhu 4
Affiliations

Affiliations

  • 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 2 Department of Medicinal Chemistry, Centaurus BioPharma Co., Ltd, Beijing, China.
  • 3 Department of Discovery Biology, Centaurus BioPharma Co., Ltd, Beijing, China.
  • 4 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. hongzhu@zju.edu.cn.
Abstract

Hepatocellular carcinoma is among the leading causes of cancer-related deaths worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met Inhibitor, cabozantinib, and a novel FAK Inhibitor, CT-707, exerted synergistic antitumor effects against hepatocellular carcinoma in vitro and in vivo Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the antitumor activity of cabozantinib. The simultaneous exposure to CT-707 effectively inhibited the activation of FAK that was induced by cabozantinib, which contributes to the synergistic effect of the combination. Furthermore, cabozantinib increased the mRNA and protein levels of Integrin α5, which is a canonical upstream of FAK, and the introduction of cilengitide to block Integrin function could abrogate FAK activation by cabozantinib, indicating that cabozantinib upregulated the phosphorylation of FAK in an integrin-dependent manner. Similar synergy was also observed on PHA-665752, another selective Met Inhibitor, indicating that this observation might be a common characteristic of MET-targeting strategies. Our findings not only favor the development of the novel FAK Inhibitor CT-707 as a therapeutic agent against hepatocellular carcinoma but also provide a new strategy of combining MET and FAK inhibitors to potentiate the Anticancer activities of these two types of agents for treating hepatocellular carcinoma patients. Mol Cancer Ther; 15(12); 2916-25. ©2016 AACR.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-109084
    99.54%, FAK抑制剂
    FAK