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 language | English |
|---|---|
| Pages (from-to) | 1483-1490 |
| Number of pages | 8 |
| Journal | Molecular Cancer Research |
| Volume | 16 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Oct 1 2018 |
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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 journal › Article
}
TY - JOUR
T1 - Thymidine kinase 1 loss confers trifluridine resistance without affecting 5-fluorouracil metabolism and cytotoxicity
AU - Edahiro, Keitaro
AU - Iimori, Makoto
AU - Kobunai, Takashi
AU - Morikawa-Ichinose, Tomomi
AU - Miura, Daisuke
AU - Kataoka, Yuki
AU - Niimi, Shinichiro
AU - Wakasa, Takeshi
AU - Saeki, Hiroshi
AU - Oki, Eiji
AU - Kitao, Hiroyuki
AU - Maehara, Yoshihiko
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85050677226&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-17-0686
DO - 10.1158/1541-7786.MCR-17-0686
M3 - Article
VL - 16
SP - 1483
EP - 1490
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 10
ER -