Journal
CANCER SCIENCE
Volume 107, Issue 2, Pages 140-148Publisher
WILEY
DOI: 10.1111/cas.12849
Keywords
ALK5 inhibitor; CML stem cells; relapse prevention; TGF- signaling; TKI resistance
Categories
Funding
- Yasuda Medical Foundation
- Mochida Memorial Foundation
- Naito Foundation
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Ministry of Science, ICT and Future Planning through the National Research Foundation, Korea
- Ministry of Education, Science and Technology, Korea
- Grants-in-Aid for Scientific Research [15H02361, 25430107, 16K07111, 15H01509] Funding Source: KAKEN
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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- 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.
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