Research Papers:

MBD4 frameshift mutation caused by DNA mismatch repair deficiency enhances cytotoxicity by trifluridine, an active antitumor agent of TAS-102, in colorectal cancer cells

Satoshi Suzuki, Moriya Iwaizumi _, Hidetaka Yamada, Tomohiro Sugiyama, Yasushi Hamaya, Takahisa Furuta, Shigeru Kanaoka, Haruhiko Sugimura, Hiroaki Miyajima, Satoshi Osawa, John M. Carethers and Ken Sugimoto

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Oncotarget. 2018; 9:11477-11488. https://doi.org/10.18632/oncotarget.22484

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Satoshi Suzuki1, Moriya Iwaizumi1, Hidetaka Yamada2, Tomohiro Sugiyama1, Yasushi Hamaya1, Takahisa Furuta3, Shigeru Kanaoka4, Haruhiko Sugimura2,7, Hiroaki Miyajima1, Satoshi Osawa5, John M. Carethers6 and Ken Sugimoto1

1First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

2Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan

3Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan

4Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan

5Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

6Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

7International Mass Imaging Center, Hamamatsu University School of Medicine, Hamamatsu, Japan

Correspondence to:

Moriya Iwaizumi, email: [email protected]

Keywords: colorectal cancer; trifluridine; MBD4; microsatellite instability; frameshift mutation

Received: January 23, 2017    Accepted: October 02, 2017    Published: November 15, 2017


Backgrounds: Trifluridine is an active antitumor component of TAS-102 that resembles 5-fluorouracil. Although patients with advanced colorectal cancer (CRC) exhibiting a mismatch repair (MMR) deficiency reportedly do not benefit from 5-fluorouracil-based chemotherapy and we previously reported that truncated methyl-CpG binding domain protein 4 (MBD4) enhances 5-fluorouracil cytotoxicity in MMR-deficient CRC cells, little is known regarding the effect of MMR deficiency on trifluridine cytotoxicity in CRC.Aim: We investigated whether trifluridine induces cytotoxicity in a DNA MMR-dependent manner and evaluated how truncated MBD4 alters trifluridine cytotoxicity.Methods: We utilized the human CRC cell lines HCT116 (hMLH1-deficient cells) and HCT116+ch3 (hMLH1-restored cells) and compared their sensitivities to trifluridine. And we established 5-fluorouracil-refractory hMLH1-deficient cells and analyzed trifluridine cytotoxicity. Finally, we established truncated MBD4 overexpressed CRC cell lines, and compared trifluridine sensitivity.Results: The sensitivities of HCT116 and HCT116+ch3 to trifluridine were comparable. 5-Fluorouracil-refractory hMLH1-deficient cells treated with trifluridine showed an equal or greater sensitivity than non-5-fluorouracil-refractory cells. Moreover, MBD4tru cells were more sensitive than the control cells to trifluridine.Conclusions: Trifluridine induces cytotoxicity independently of the DNA MMR status as well as under 5-fluorouracil-refractory conditions, and the MBD4 frameshift mutation enhances trifluridine cytotoxicity.

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