Novel oral transforming growth factor‐β signaling inhibitor EW‐7197 eradicates CML‐initiating cells |
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| Authors: | Kazuhito Naka Kaori Ishihara Yoshie Jomen Cheng Hua Jin Dong‐Hyun Kim Yoon‐Kang Gu Eun‐Sook Jeong Shaoguang Li Daniela S. Krause Dong‐Wook Kim Eunjin Bae Yoshihiro Takihara Atsushi Hirao Hiroko Oshima Masanobu Oshima Akira Ooshima Yhun Yhong Sheen Seong‐Jin Kim Dae‐Kee Kim |
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| Affiliation: | 1. Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;2. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;3. Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea;4. Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea;5. Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA;6. Institute for Tumor Biology and Experimental Therapy, Georg Speyer Haus, Goethe University, Frankfurt, Germany;7. Department of Hematology, Seoul St. Mary's Hospital, Cancer Research Institute, The Catholic University of Korea, Seoul, Korea;8. CHA Cancer Institute and Department of Biomedical Science, CHA University, Seongnam, Korea;9. Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;10. Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan;11. College of Pharmacy, Ewha Womans University, Seoul, Korea |
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| 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. |
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| Keywords: | ALK5 inhibitor CML stem cells relapse prevention TGF‐β signaling TKI resistance |
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