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

Autor: Daisuke Sawa, Hiroshi Moritake, Naoki Sameshima, Yusuke Saito, Ai Yamada, Mariko Kinoshita, Sachiyo Kamimura, Takao Konomoto, Hiroyuki Nunoi
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Cell cycle checkpoint
medicine.medical_treatment
Morpholines
Apoptosis
Sarcoma
Ewing
lcsh:RC254-282
Metastasis
Receptor
IGF Type 1
Focal adhesion
03 medical and health sciences
Mice
0302 clinical medicine
Cell Line
Tumor
medicine
Animals
Humans
metastasis
Radiology
Nuclear Medicine and imaging
Phosphorylation
Receptor
Protein kinase B
Protein Kinase Inhibitors
insulin‐like growth factor‐I receptor
Neoplasm Staging
Original Research
Cancer Biology
Dose-Response Relationship
Drug
Chemistry
Growth factor
TAE226
focal adhesion kinase
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Xenograft Model Antitumor Assays
Disease Models
Animal
030104 developmental biology
Oncology
Metastatic Ewing Sarcoma
Tyrosine kinase 2
030220 oncology & carcinogenesis
Focal Adhesion Protein-Tyrosine Kinases
Cancer research
Biomarkers
Ewing sarcoma
Zdroj: Cancer Medicine
Cancer Medicine, Vol 8, Iss 18, Pp 7809-7821 (2019)
ISSN: 2045-7634
Popis: 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.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje