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

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

doi:10.1111/cas.12849

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

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

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English
Pages (from-to)	140-148
Number of pages	9
Journal	Cancer Science
Volume	107
Issue number	2
DOIs	https://doi.org/10.1111/cas.12849
State	Published - 1 Feb 2016

Bibliographical note

Publisher Copyright:
© 2016 Japanese Cancer Association.

Keywords

ALK5 inhibitor
CML stem cells
Relapse prevention
TGF-β signaling
TKI resistance

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Naka, K., Ishihara, K., Jomen, Y., Jin, C. H., Kim, D. H., Gu, Y. K., Jeong, E. S., Li, S., Krause, D. S., Kim, D. W., Bae, E., Takihara, Y., Hirao, A., Oshima, H., Oshima, M., Ooshima, A., Sheen, Y. Y., Kim, S. J., & Kim, D. K. (2016). Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells. Cancer Science, 107(2), 140-148. https://doi.org/10.1111/cas.12849

@article{2a3fa9bfc6804517bd866bd8ce046704,

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.",

keywords = "ALK5 inhibitor, CML stem cells, Relapse prevention, TGF-β signaling, TKI resistance",

author = "Kazuhito Naka and Kaori Ishihara and Yoshie Jomen and Jin, {Cheng Hua} and Kim, {Dong Hyun} and Gu, {Yoon Kang} and Jeong, {Eun Sook} and Shaoguang Li and Krause, {Daniela S.} and Kim, {Dong Wook} and Eunjin Bae and Yoshihiro Takihara and Atsushi Hirao and Hiroko Oshima and Masanobu Oshima and Akira Ooshima and Sheen, {Yhun Yhong} and Kim, {Seong Jin} and Kim, {Dae Kee}",

note = "Publisher Copyright: {\textcopyright} 2016 Japanese Cancer Association.",

year = "2016",

month = feb,

day = "1",

doi = "10.1111/cas.12849",

language = "English",

volume = "107",

pages = "140--148",

journal = "Cancer Science",

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Naka, K, Ishihara, K, Jomen, Y, Jin, CH, Kim, DH, Gu, YK, Jeong, ES, Li, S, Krause, DS, Kim, DW, Bae, E, Takihara, Y, Hirao, A, Oshima, H, Oshima, M, Ooshima, A, Sheen, YY, Kim, SJ & Kim, DK 2016, 'Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells', Cancer Science, vol. 107, no. 2, pp. 140-148. https://doi.org/10.1111/cas.12849

TY - JOUR

T1 - Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells

AU - Naka, Kazuhito

AU - Ishihara, Kaori

AU - Jomen, Yoshie

AU - Jin, Cheng Hua

AU - Kim, Dong Hyun

AU - Gu, Yoon Kang

AU - Jeong, Eun Sook

AU - Li, Shaoguang

AU - Krause, Daniela S.

AU - Kim, Dong Wook

AU - Bae, Eunjin

AU - Takihara, Yoshihiro

AU - Hirao, Atsushi

AU - Oshima, Hiroko

AU - Oshima, Masanobu

AU - Ooshima, Akira

AU - Sheen, Yhun Yhong

AU - Kim, Seong Jin

AU - Kim, Dae Kee

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

KW - ALK5 inhibitor

KW - CML stem cells

KW - Relapse prevention

KW - TGF-β signaling

KW - TKI resistance

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U2 - 10.1111/cas.12849

DO - 10.1111/cas.12849

M3 - Article

C2 - 26583567

AN - SCOPUS:84958923762

SN - 1347-9032

VL - 107

SP - 140

EP - 148

JO - Cancer Science

JF - Cancer Science

IS - 2

ER -

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

Abstract

Bibliographical note

Keywords

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