Reference Detail

Ref Type

Journal Article

PMID

(27638856)

Authors

Wang DD, Chen Y, Chen ZB, Yan FJ, Dai XY, Ying MD, Cao J, Ma J, Luo PH, Han YX, Peng Y, Sun YH, Zhang H, He QJ, Yang B, Zhu H

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	12	2016 Dec	2916-2925	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Conteltinib	Conteltinib	8	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Conteltinib		CT-707\|CT 707	ALK Inhibitor 32 FAK inhibitor 15 YAP Inhibitor 3	Conteltinib (CT-707) is a kinase inhibitor of FAK (PTK2), PYK2 (PTK2B), ALK, and YAP1 (PMID: 29669759), which may result in antitumor activity including inhibition of both tumor growth and metastasis (PMID: 27638856, PMID: 30381078).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References