ABT-869 inhibits the proliferation of Ewing Sarcoma cells and suppresses platelet-derived growth factor receptor beta and c-KIT signaling pathways

Mol Cancer Ther. 2010 Mar;9(3):653-60. doi: 10.1158/1535-7163.MCT-09-0812. Epub 2010 Mar 2.

Abstract

The 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 <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 multitargeted small-molecule inhibitor that targets Fms-like tyrosine kinase-3, c-KIT, vascular endothelial growth receptors, 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 and 2 mumol/L after 72 h of treatment, respectively. The phosphorylation of PDGFRbeta, c-KIT, and extracellular signal-regulated kinases 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 show that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFRbeta and c-KIT pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology*
  • Cell Proliferation / drug effects*
  • Down-Regulation / drug effects
  • Humans
  • Indazoles / pharmacology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phenylurea Compounds / pharmacology*
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Sarcoma, Ewing / metabolism
  • Sarcoma, Ewing / pathology*
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Indazoles
  • N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N1-(2-fluoro-5-methylphenyl)urea
  • Phenylurea Compounds
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor beta