title: Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells.
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.
authors.affiliation: Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.|Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Naka
authors.affiliation: Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ishihara
authors.affiliation: Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Jomen
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Cheng Hua
authors.initials: CH
authors.lastname: Jin
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
authors.forename: Yoon-Kang
authors.initials: YK
authors.lastname: Gu
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Jeong
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg Speyer Haus, Goethe University, Frankfurt, Germany.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Krause
authors.affiliation: Department of Hematology, Seoul St. Mary's Hospital, Cancer Research Institute, The Catholic University of Korea, Seoul, Korea.
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.|CHA Cancer Institute and Department of Biomedical Science, CHA University, Seongnam, Korea.
authors.forename: Eunjin
authors.initials: E
authors.lastname: Bae
authors.affiliation: Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takihara
authors.affiliation: Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oshima
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.affiliation: CHA Cancer Institute and Department of Biomedical Science, CHA University, Seongnam, Korea.
authors.forename: Akira
authors.initials: A
authors.lastname: Ooshima
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Yhun Yhong
authors.initials: YY
authors.lastname: Sheen
authors.affiliation: CHA Cancer Institute and Department of Biomedical Science, CHA University, Seongnam, Korea.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011724:Pyridazines / Q000008:administration & dosage; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014230:Triazoles; C545373:ponatinib; C000590371:vactosertib; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
keywords: ALK5 inhibitor; CML stem cells; TGF-β signaling; TKI resistance; relapse prevention