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

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.

Focal adhesion kinase confers pro‐migratory and antiapoptotic properties and is a potential therapeutic target in Ewing sarcoma

“…One report previously identified FAK as a potential therapeutic target in EwS by the use of high-throughput tyrosine kinase activity profiling (Crompton et al, 2013). The same group just recently showed that synergistic inhibition of FAK and Aurora B kinase effectively impairs EwS growth in multiple xenograft models, while another study revealed that dual inhibition of FAK and insulin-like growth factor-I receptor acts synergistically with conventional chemotherapy to induce apoptosis and impair invasion of EwS in vitro and in vivo (Moritake et al, 2019;Wang et al, 2019). In line, another report showed that miR-138, via targeting FAK, inhibits proliferation and mobility and induces anoikis of EwS cells (Tanaka et al, 2016).…”

The Role of IGF/IGF-IR-Signaling and Extracellular Matrix Effectors in Bone Sarcoma Pathogenesis

“…In EWS mouse models, TAE226 was demonstrated to inhibit the local growth of primary tumors and hinder metastasis. Furthermore, the combination of TAE226 and chemotherapy agents showed that TAE226 could exhibit a synergistic effect with conventional chemotherapy and be possibly beneficial for EWS relapse and metastatic patients [87]. Moreover, a recent study demonstrated that CIC-DUX4 Ewing's sarcoma, an aggressive and often fatal high-grade childhood sarcoma, metastasizes to the lung, utilizing an autocrine IGF-IR/AKT signaling axis [88].…”

Focal adhesion kinase inhibitors, a heavy punch to cancer

“…TAE226, also known as NVP-226, inhibits FAK activity by blocking the linkage between FAK phosphorylation sites of Tyr397 and Tyr861 and ATP binding pocket. TAE226 has shown anti-tumor effects in preclinical in vivo and in vitro assays in non-small cell lung cancer (NSCLC) [ 34 ], Ewing’s Sarcoma (EWS) [ 35 ], Ph + Acute lymphoblastic leukemia (Ph + ALL) [ 36 ], oral squamous cell carcinoma (OSCC) [ 37 ], colorectal carcinoma [ 38 ] and pancreatic ductal adenocarcinoma (PDAC) [ 39 ]. Nevertheless, TAE226 had not been approved for clinical trials due to serious side effects on glucose metabolism [ 40 ].…”

“…In Ewing's sarcoma, TAE226 enhanced the efficacy of conventional chemotherapy [ 35 ]. PF-562,271 and Aurora kinase inhibitors synergistically inhibited the proliferation of Ewing’s sarcoma cells and significantly suppressed tumor progression [ 92 ].…”