Journal
MOLECULAR ONCOLOGY
Volume 16, Issue 14, Pages 2747-2765Publisher
WILEY
DOI: 10.1002/1878-0261.13270
Keywords
chronic myeloid leukemia; combined treatment; EPHB4; vandetanib
Categories
Funding
- National Natural Science Foundation of China [81773772]
- Natural Science Basic Research Program of Shaanxi Province [2022JM-574]
- Fundamental Research Funds for the Central Universities [xzy012019078]
Ask authors/readers for more resources
EPHB4 plays an oncogenic role in CML, as its knockdown inhibits cell growth and increases sensitivity to imatinib. Vandetanib, by targeting EPHB4, shows potential in inhibiting CML growth and overcoming imatinib resistance.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available