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|Ref Type||Journal Article|
|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||Molecular cancer therapeutics|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CT-707||ALK Inhibitor 23 FAK inhibitor 13 YAP Inhibitor 2||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|
|Unknown unknown||hepatocellular carcinoma||not applicable||CT-707 + PHA-665752||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of PHA-665752 and CT-707 resulted in synergism in hepatocellular carcinoma cells in culture, demonstrating near complete cell death (PMID: 27638856).||27638856|
|Unknown unknown||hepatocellular carcinoma||not applicable||Cabozantinib + CT-707||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of Cometriq (Cabometyx, cabozantinib) and CT-707 resulted in synergism in hepatocellular carcinoma cells, demonstrating increased apoptosis and inhibition of colony formation in culture and decreased tumor weight in xenograft models (PMID: 27638856).||27638856|