論文

査読有り 本文へのリンクあり
2020年6月1日

Synthetic Lethality with Trifluridine/Tipiracil and Checkpoint Kinase 1 Inhibitor for Esophageal Squamous Cell Carcinoma

Molecular cancer therapeutics
  • Shinya Ohashi
  • ,
  • Osamu Kikuchi
  • ,
  • Yukie Nakai
  • ,
  • Tomomi Ida
  • ,
  • Tomoki Saito
  • ,
  • Yuki Kondo
  • ,
  • Yoshihiro Yamamoto
  • ,
  • Yosuke Mitani
  • ,
  • Trang H. Nguyen Vu
  • ,
  • Keita Fukuyama
  • ,
  • Hiroshi Tsukihara
  • ,
  • Norihiko Suzuki
  • ,
  • Manabu Muto

19
6
開始ページ
1363
終了ページ
1372
記述言語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/1535-7163.MCT-19-0918

©2020 American Association for Cancer Research. Esophageal squamous cell carcinoma (ESCC) is a disease characterized by a high mutation rate of the TP53 gene, which plays pivotal roles in the DNA damage response (DDR) and is regulated by checkpoint kinase (CHK) 2. CHK1 is another key DDR-related protein, and its selective inhibition is suggested to be particularly sensitive to TP53-mutated cancers, because a loss of both pathways (CHK1 and/or CHK2-p53) is lethal due to the serious impairment of DDR. Such a therapeutic strategy is termed synthetic lethality. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and prexasertib (CHK1 inhibitor) as a treatment for ESCC. Trifluridine is a key component of the antitumor drug combination with trifluridine/tipiracil (an inhibitor of trifluridine degradation), also known as TAS-102. In this study, we demonstrate that trifluridine increases CHK1 phosphorylation in ESCC cells combined with a reduction of the S-phase ratio as well as the induction of ssDNA damage. Because CHK1 phosphorylation is considered to be induced as DDR for trifluridine-mediated DNA damage, we examined the effects of CHK1 inhibition on trifluridine treatment. Consequently, CHK1 inhibition by short hairpin RNA or treatment with the CHK1 inhibitor, prexasertib, markedly enhanced trifluridine-mediated DNA damage, represented by an increase of γH2AX expression. Moreover, the combination of trifluridine/tipiracil and CHK1 inhibition significantly suppressed tumor growth of ESCC-derived xenograft tumors. Furthermore, the combination of trifluridine and prexasertib enhanced radiosensitivity both in vitro and in vivo Thus, the combination of trifluridine/tipiracil and a CHK1 inhibitor exhibits effective antitumor effects, suggesting a novel therapeutic strategy for ESCC.

リンク情報
DOI
https://doi.org/10.1158/1535-7163.MCT-19-0918
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32371587
Scopus
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85085903833&origin=inward 本文へのリンクあり
Scopus Citedby
https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85085903833&origin=inward
ID情報
  • DOI : 10.1158/1535-7163.MCT-19-0918
  • eISSN : 1538-8514
  • PubMed ID : 32371587
  • SCOPUS ID : 85085903833

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