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

作者：Suzuki Satoshi; Iwaizumi Moriya; Yamada Hidetaka; Sugiyama Tomohiro; Hamaya Yasushi; Furuta Takahisa; Kanaoka Shigeru; Sugimura Haruhiko; Miyajima Hiroaki; Osawa Satoshi; Carethers John M; Sugimoto Ken

来源：ONCOTARGET, 2018, 9(14): 11477-11488.

DOI：10.18632/oncotarget.22484

• MBD4
• colorectal cancer
• frameshift mutation
• microsatellite instability
• trifluridine

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.

• 单位
  university of michigan