Vandetanib drives growth arrest and promotes sensitivity to imatinib in chronic myeloid leukemia by targeting ephrin type‐B receptor 4

• Published in: Molecular oncology Vol. 16; no. 14; pp. 2747 - 2765
• Main Authors: Ma, Weina, Zhu, Man, Wang, Bo, Gong, Zhengyan, Du, Xia, Yang, Tianfeng, Shi, Xianpeng, Dai, Bingling, Zhan, Yingzhuan, Zhang, Dongdong, Ji, Yanhong, Wang, Yang, Li, Song, Zhang, Yanmin
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.07.2022; John Wiley and Sons Inc; Wiley
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Apoptosis; Biotechnology; Cell growth; Chromatography; Chronic myeloid leukemia; combined treatment; Drugs; EPHB4; EphB4 protein; Epidermal growth factor; Extracellular signal-regulated kinase; FDA approval; Gene expression; Hydrophobicity; Imatinib; Immunoglobulins; Kinases; Laboratory animals; Leukemia; MAP kinase; Myeloid leukemia; Phosphatase; Proteasomes; Protein-tyrosine kinase; Proteins; siRNA; Software; Transfection; Tumors; Ubiquitin; vandetanib; Vascular endothelial growth factor; Xenografts; United States > US; China; Japan; Vandetanib; Combined treatment; Chronic myeloid leukemia; EPHB4
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13270

The oncogenic role of ephrin type‐B receptor 4 (EPHB4) has been reported in many types of tumors, including chronic myeloid leukemia (CML). Here, we found that CML patients have a higher EPHB4 expression level than healthy subjects. EPHB4 knockdown inhibited growth of K562 cells (a human immortalized myelogenous leukemia cell line). In addition, transient transfection of EPHB4 siRNA led to sensitization to imatinib. These growth defects could be fully rescued by EPHB4 transfection. To identify an EPHB4‐specific inhibitor with the potential of rapid translation into the clinic, a pool of clinical compounds was screened and vandetanib was found to be most sensitive to K562 cells, which express a high level of EPHB4. Vandetanib mainly acts on the intracellular tyrosine kinase domain and interacts stably with a hydrophobic pocket. Furthermore, vandetanib downregulated EPHB4 protein via the ubiquitin‐proteasome pathway and inhibited PI3K/AKT and MAPK/ERK signaling pathways in K562 cells. Vandetanib alone significantly inhibited tumor growth in a K562 xenograft model. Furthermore, the combination of vandetanib and imatinib exhibited enhanced and synergistic growth inhibition against imatinib‐resistant K562 cells in vitro and in vivo. These findings suggest that vandetanib drives growth arrest and overcomes the resistance to imatinib in CML via targeting EPHB4. Our study has established vandetanib as a potent inhibitor of EPHB4. Inhibition of EPHB4 by vandetanib drives growth arrest and promotes the sensitivity of imatinib‐resistant cells to imatinib in CML. Combined treatment with vandetanib and imatinib may provide a new therapeutic strategy to overcome acquired drug resistance in patients with CML.