Thymidine kinase 1 loss confers trifluridine resistance without affecting 5-fluorouracil metabolism and cytotoxicity

Keitaro Edahiro, Makoto Iimori, Takashi Kobunai, Tomomi Morikawa-Ichinose, Daisuke Miura, Yuki Kataoka, Shinichiro Niimi, Takeshi Wakasa, Hiroshi Saeki, Eiji Oki, Hiroyuki Kitao, Yoshihiko Maehara

Research output: Contribution to journalArticle

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Abstract

Acquired resistance to therapeutic drugs is a serious problem for patients with cancer receiving systemic treatment. Experimentally, drug resistance is established in cell lines in vitro by repeated, continuous exposure to escalating concentrations of the drug; however, the precise mechanism underlying the acquired resistance is not always known. Here, it is demonstrated that the human colorectal cancer cell line DLD1 with acquired resistance to trifluridine (FTD), a key component of the novel, orally administered nucleoside analoguetype chemotherapeutic drug trifluridine/tipiracil, lacks functional thymidine kinase 1 (TK1) expression because of one nonsense mutation in the coding exon. Targeted disruption of the TK1 gene also conferred severe FTD resistance, indicating that the loss of TK1 protein expression is the primary cause of FTD resistance. Both FTD-resistant DLD1 cells and DLD1- TK1 cells exhibited similar 5-fluorouracil (5-FU) sensitivity to that of the parental DLD1 line. The quantity of cellular pyrimidine nucleotides in these cells and the kinetics of thymidylate synthase ternary complex formation in 5-FU- treated cells is similar to DLD1 cells, indicating that 5-FU metabolism and cytotoxicity were unaffected. The current data provide molecular-based evidence that acquired resistance to FTD does not confer 5-FU resistance, implying that 5-FU- based chemotherapy would be effective even in tumors that become refractory to FTD during trifluridine/tipiracil treatment.

Original languageEnglish
Pages (from-to)1483-1490
Number of pages8
JournalMolecular Cancer Research
Volume16
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

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Trifluridine
Fluorouracil
Pyrimidine Nucleotides
Pharmaceutical Preparations
Cell Line
Thymidylate Synthase
Nonsense Codon
Nucleosides
Drug Resistance
Colorectal Neoplasms
Exons
Neoplasms
Therapeutics
thymidine kinase 1
Drug Therapy
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Thymidine kinase 1 loss confers trifluridine resistance without affecting 5-fluorouracil metabolism and cytotoxicity. / Edahiro, Keitaro; Iimori, Makoto; Kobunai, Takashi; Morikawa-Ichinose, Tomomi; Miura, Daisuke; Kataoka, Yuki; Niimi, Shinichiro; Wakasa, Takeshi; Saeki, Hiroshi; Oki, Eiji; Kitao, Hiroyuki; Maehara, Yoshihiko.

In: Molecular Cancer Research, Vol. 16, No. 10, 01.10.2018, p. 1483-1490.

Research output: Contribution to journalArticle

Edahiro, K, Iimori, M, Kobunai, T, Morikawa-Ichinose, T, Miura, D, Kataoka, Y, Niimi, S, Wakasa, T, Saeki, H, Oki, E, Kitao, H & Maehara, Y 2018, 'Thymidine kinase 1 loss confers trifluridine resistance without affecting 5-fluorouracil metabolism and cytotoxicity' Molecular Cancer Research, vol. 16, no. 10, pp. 1483-1490. https://doi.org/10.1158/1541-7786.MCR-17-0686
Edahiro, Keitaro ; Iimori, Makoto ; Kobunai, Takashi ; Morikawa-Ichinose, Tomomi ; Miura, Daisuke ; Kataoka, Yuki ; Niimi, Shinichiro ; Wakasa, Takeshi ; Saeki, Hiroshi ; Oki, Eiji ; Kitao, Hiroyuki ; Maehara, Yoshihiko. / Thymidine kinase 1 loss confers trifluridine resistance without affecting 5-fluorouracil metabolism and cytotoxicity. In: Molecular Cancer Research. 2018 ; Vol. 16, No. 10. pp. 1483-1490.
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