ABT-869 Inhibits Proliferation of Ewing Sarcoma cells and Suppresses PDGFRβ and c-KIT Signaling Pathways

• Published in: Molecular cancer therapeutics 2010-03, Vol.9 (3), p.653-660
• Main Authors: Ikeda, Alan K., Judelson, Dejah R., Federman, Noah, Glaser, Keith B., Landaw, Elliot M., Denny, Christopher T, Sakamoto, Kathleen M.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-09-0812

Ewing Sarcoma (EWS) family of tumors is one of the most common tumors diagnosed in children and adolescents and is characterized by a translocation involving the EWS gene. Despite advances in chemotherapy, the prognosis of metastatic EWS is poor with an overall survival of less than 30% after 5 years. EWS tumor cells express the receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR) and c-KIT. ABT-869 is a multi-targeted small molecule inhibitor that targets Fms-like tyrosine kinase-3 (FLT-3), c-KIT, vascular endothelial growth receptors (VEGFR) and PDGFRs. To determine the potential therapeutic benefit of ABT-869 in EWS cells, we examined the effects of ABT-869 on EWS cell lines and xenograft mouse models. ABT-869 inhibited the proliferation of two EWS cell lines, A4573 and TC71, at an IC 50 of 1.25 μM and 2 μM after 72 hours of treatment, respectively. Phosphorylation of PDGFRβ, c-KIT, and ERKs was also inhibited. To examine the effects of ABT-869 in vivo , the drug was given to mice injected with EWS cells. We observed inhibition of growth of EWS tumor cells in a xenograft mouse model and prolonged survival in a metastatic mouse model of EWS. Therefore, our in vitro and in vivo studies demonstrate that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFRβ and c-KIT pathways.