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

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TAE226, a dual inhibitor of focal adhesion kinase and insulin-like growth factor-I receptor, is effective for Ewing sarcoma.
Cancer Medicine ( IF 2.9 ) Pub Date : 2019-11-06 , DOI: 10.1002/cam4.2647
Hiroshi Moritake ₁ , Yusuke Saito ₁ , Daisuke Sawa ₁ , Naoki Sameshima ₂ , Ai Yamada ₁ , Mariko Kinoshita ₁ , Sachiyo Kamimura ₁ , Takao Konomoto ₁ , Hiroyuki Nunoi ₁

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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.

中文翻译：

TAE226是一种粘着斑激酶和胰岛素样生长因子-I受体的双重抑制剂，对尤因肉瘤有效。

复发性和转移性尤因肉瘤（EWS）的预后极差。因此，重要的是在这些难治性疾病中鉴定肿瘤特异性靶标。EWS细胞系中的高粘着斑激酶（FAK）转录本表达水平是已知的。TAE226是FAK和胰岛素样生长因子I受体（IGF-IR）的双重抑制剂，而PF-562,271是FAK和富含脯氨酸的酪氨酸激酶2的双重抑制剂。我们比较了TAE226和PF-562,271的细胞毒性。朝向三个EWS细胞系。与PF-562,271相比，TAE226强烈抑制了三种细胞系的增殖。此外，我们研究了TAE226的功效及其对抗EWS的作用机理。建立了具有FAK和IGF-1R抑制的稳定的EWS细胞系，微阵列分析显示各种途径的表达失调。TAE226处理EWS细胞系可诱导细胞周期停滞，凋亡，AKT去磷酸化和抑制侵袭。我们证明，使用小鼠模型，TAE226可以显着抑制原发性肿瘤的局部生长和EWS中的转移。此外，TAE226和常规化学疗法的结合被证明具有协同作用。TAE226可能是未来将为复发和转移性EWS肿瘤患者开发的候选单药或联合治疗药物。

更新日期：2019-11-06

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