Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells

Cancer Sci. 2016 Feb;107(2):140-8. doi: 10.1111/cas.12849. Epub 2016 Jan 26.

Abstract

Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia-initiating cells (CML-LICs). However, little is known about the therapeutic benefits such CML-LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW-7197, an orally bioavailable transforming growth factor-β signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML-LICs in vivo. Compared to TKI treatment alone, administration of TKI plus EW-7197 to CML-affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW-7197 plus TKI was effective in eliminating CML-LICs even if they expressed the TKI-resistant T315I mutant BCR-ABL1 oncogene. Collectively, these results indicate that EW-7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML-LICs.

Keywords: ALK5 inhibitor; CML stem cells; TGF-β signaling; TKI resistance; relapse prevention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Humans
  • Imidazoles / administration & dosage
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Protein Kinase Inhibitors / administration & dosage
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Pyridazines / administration & dosage
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Transfection
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Triazoles / pharmacology*

Substances

  • Aniline Compounds
  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridazines
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Triazoles
  • ponatinib
  • vactosertib
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse