TAE226, a dual inhibitor of focal adhesion kinase and insulin‐like growth factor‐I receptor, is effective for Ewing sarcoma

• Published in: Cancer medicine (Malden, MA) MA), 2019-12, Vol.8 (18), p.7809-7821
• Main Authors: Moritake, Hiroshi, Saito, Yusuke, Sawa, Daisuke, Sameshima, Naoki, Yamada, Ai, Kinoshita, Mariko, Kamimura, Sachiyo, Konomoto, Takao, Nunoi, Hiroyuki
• Format: Article
• Language: English
• Subjects: AKT protein; Animal models; Animals; Apoptosis; Apoptosis - drug effects; Biomarkers; Bone marrow; Cancer Biology; Cancer therapies; Cell cycle; Cell growth; Cell Line, Tumor; Chemotherapy; Clinical trials; Cytotoxicity; Dephosphorylation; Disease Models, Animal; DNA microarrays; Dose-Response Relationship, Drug; Enzyme inhibitors; Ewing sarcoma; Ewing's sarcoma; Ewings sarcoma; Fibroblasts; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors; Growth factors; Humans; Immunoglobulins; Insulin; insulin‐like growth factor‐I receptor; Kinases; Lymphoma; Medical prognosis; Metastases; Metastasis; Mice; Morpholines - pharmacology; Mutation; Neoplasm Staging; Original Research; Pediatrics; Penicillin; Phosphorylation; Proline; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proteins; Receptor, IGF Type 1 - antagonists & inhibitors; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - metabolism; Sarcoma, Ewing - pathology; TAE226; Transcription; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.2647

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. Systemic TAE226 treatment potently reduced the size of local tumors and inhibited micrometastasis in vivo through cell cycle inhibition, induction of apoptosis, and inhibition of AKT signaling. Furthermore, combined therapy with TAE226 and conventional anticancer drugs for EWS has synergistic anticancer effects. Overall, the results of the present study suggest that TAE226 is a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.