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Small Molecule Therapeutics

Tankyrase Inhibitors Target Colorectal Cancer Stem Cells via AXIN-Dependent Downregulation of c-KIT Tyrosine Kinase

Myung-Kyu Jang, Tetsuo Mashima and Hiroyuki Seimiya
Myung-Kyu Jang
1Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
2Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
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Tetsuo Mashima
1Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
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Hiroyuki Seimiya
1Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
2Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
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  • ORCID record for Hiroyuki Seimiya
  • For correspondence: hseimiya@jfcr.or.jp
DOI: 10.1158/1535-7163.MCT-19-0668 Published March 2020
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Abstract

Cancer stem cells (CSC) constitute heterogeneous cell subpopulations of a tumor. Although targeting CSCs is important for cancer eradication, no clinically approved drugs that target CSCs have been established. Tankyrase poly(ADP-ribosyl)ates and destabilizes AXIN, a negative regulator of β-catenin, and promotes β-catenin signaling. Here, we report that tankyrase inhibitors downregulate c-KIT tyrosine kinase and inhibit the growth of CD44-positive colorectal CSCs. c-KIT expression in CD44-positive subpopulations of colorectal cancer COLO-320DM cells is associated with their tumor-initiating potential in vivo. Tankyrase inhibitors downregulate c-KIT expression in established cell lines, such as COLO-320DM and DLD-1, and colorectal cancer patient–derived cells. These effects of tankyrase inhibitors are caused by reducing the recruitment of SP1 transcription factor to the c-KIT gene promoter and depend on AXIN2 stabilization but not β-catenin downregulation. Whereas c-KIT knockdown inhibits the growth of CD44-positive COLO-320DM cells, c-KIT overexpression in DLD-1 cells confers resistance to tankyrase inhibitors. Combination of a low-dose tankyrase inhibitor and irinotecan significantly inhibited the growth of COLO-320DM tumors in a mouse xenograft model. These observations suggest that tankyrase inhibitors target c-KIT–positive colorectal CSCs and provide a novel therapeutic strategy for cancer.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:765–76

  • Received July 4, 2019.
  • Revision received November 7, 2019.
  • Accepted December 27, 2019.
  • Published first January 6, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (3)
March 2020
Volume 19, Issue 3
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Tankyrase Inhibitors Target Colorectal Cancer Stem Cells via AXIN-Dependent Downregulation of c-KIT Tyrosine Kinase
Myung-Kyu Jang, Tetsuo Mashima and Hiroyuki Seimiya
Mol Cancer Ther March 1 2020 (19) (3) 765-776; DOI: 10.1158/1535-7163.MCT-19-0668

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Tankyrase Inhibitors Target Colorectal Cancer Stem Cells via AXIN-Dependent Downregulation of c-KIT Tyrosine Kinase
Myung-Kyu Jang, Tetsuo Mashima and Hiroyuki Seimiya
Mol Cancer Ther March 1 2020 (19) (3) 765-776; DOI: 10.1158/1535-7163.MCT-19-0668
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Molecular Cancer Therapeutics
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