RRC ID 59949
Author Moritake H, Saito Y, Sawa D, Sameshima N, Yamada A, Kinoshita M, Kamimura S, Konomoto T, Nunoi H.
Title TAE226, a dual inhibitor of focal adhesion kinase and insulin-like growth factor-I receptor, is effective for Ewing sarcoma.
Journal Cancer Med
Abstract The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor-specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin-like growth factor-I receptor (IGF-IR), while PF-562,271 is a dual inhibitor of FAK and proline-rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF-562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF-562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF-IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.
Volume 8(18)
Pages 7809-7821
Published 2019-12-1
DOI 10.1002/cam4.2647
PMID 31692287
PMC PMC6912025
MeSH Animals Apoptosis / drug effects Biomarkers Cell Line, Tumor Disease Models, Animal Dose-Response Relationship, Drug Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors* Humans Mice Morpholines / pharmacology* Neoplasm Staging Phosphorylation Protein Kinase Inhibitors / pharmacology* Receptor, IGF Type 1 / antagonists & inhibitors* Sarcoma, Ewing / drug therapy Sarcoma, Ewing / metabolism* Sarcoma, Ewing / pathology Xenograft Model Antitumor Assays
IF 3.357
Times Cited 3
Human and Animal Cells HS-Os-1(RCB2229)