Cytotoxicity of trifluridine correlates with the thymidine kinase 1 expression level

Kataoka, Yuki; Iimori, Makoto; Niimi, Shinichiro; Tsukihara, Hiroyuki; Wakasa, Takeshi; Saeki, Hiroshi; Oki, Eiji; Maehara, Yoshihiko; Kitao, Hiroyuki

doi:10.1038/s41598-019-44399-6

Cited by 16 publications

(18 citation statements)

References 23 publications

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“…A representative selection of references with a high biosimilarity to DFO is depicted in Figure 4, including the kinase inhibitor roscovitine, [25] the nucleoside analogue trifluridine, [26] the DNA topoisomerase 1 inhibitor topotecan, the DNA intercalating agent doxorubicin and the iron chelator ciclopirox. Beyond the high biosimilarity to DFO (Figure 3), these references also exhibit a high compound cross‐similarity (Table S5) and define a CPA cluster based on a similar morphological phenotype.…”

Section: Resultsmentioning

confidence: 99%

“…[23] Thus, the biosimilarity of iron-chelating agents and nucleoside or folic acid analogues, topoisomerase-, MAP kinase p38-, CDK-, PARP-, LSD1-and MMP-2 inhibitors and the D1 dopamine receptor agonist in the CPA is most likely not based on modulation of a similar target, that is, by direct interaction with proteins, but rather on a same MoA, that is, induction of cell-cycle arrest. [23,24] A representative selection of references with a high biosimilarity to DFO is depicted in Figure 4, including the kinase inhibitor roscovitine, [25] the nucleoside analogue trifluridine, [26] the DNA topoisomerase 1 inhibitor topotecan, the DNA intercalating agent doxorubicin and the iron chelator ciclopirox. Beyond the high biosimilarity to DFO (Figure 3), these references also exhibit a high compound cross-similarity (Table S5) and define a CPA cluster based on a similar morphological phenotype.…”

Section: Identification Of References With High Biosimilarity To Dfomentioning

confidence: 99%

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Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets

et al. 2020

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Unbiased morphological profiling of bioactivity, for example, in the cell painting assay (CPA), enables the identification of a small molecule's mode of action based on its similarity to the bioactivity of reference compounds, irrespective of the biological target or chemical similarity. This is particularly important for small molecules with nonprotein targets as these are rather difficult to identify with widely employed target-identification methods. We employed morphological profiling using the CPA to identify compounds that are biosimilar to the iron chelator deferoxamine. Structurally different compounds with different annotated cellular targets provoked a shared physiological response, thereby defining a cluster based on their morphological fingerprints. This cluster is based on a shared mode of action and not on a shared target, that is, cell-cycle modulation in the S or G2 phase. Hierarchical clustering of morphological fingerprints revealed subclusters that are based on the mechanism of action and could be used to predict target-related bioactivity.

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Section: Resultsmentioning

confidence: 99%

Section: Identification Of References With High Biosimilarity To Dfomentioning

confidence: 99%

Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets

et al. 2020

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“…6C ( 23 – 25 ). Therefore, TK is a predictive factor for the efficacy of FTD ( 26 – 28 ). In the present study, 5FU-resistant LS174T/5FUR cells showed decreased sensitivity to FdUMP, and it appears to be difficult to overcome this type of 5FU resistance by 5FU derivatives.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of acquired 5FU resistance and strategy for overcoming 5FU resistance focusing on 5FU metabolism in colon cancer cell lines

et al. 2021

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Fluorouracil (5FU) is converted to its active metabolite fluoro-deoxyuridine monophosphate (FdUMP) through the orotate phosphoribosyl transferase (OPRT)-ribonucleotide reductase (RR) pathway and thymidine phosphatase (TP)-thymidine kinase (TK) pathway and inhibits thymidylate synthase (TS), leading to inhibition of thymidine monophosphate (dTMP) synthesis through a de novo pathway. We investigated the mechanism of 5FU resistance and strategies to overcome it by focusing on 5FU metabolism. Colon cancer cell lines SW48 and LS174T and 5FU-resistant cell lines SW48/5FUR and LS174T/5FUR were used. FdUMP amount was measured by western blotting. The FdUMP synthetic pathway was investigated by combining TP inhibitor (tipiracil hydrochloride; TPI) or RR inhibitor (hydroxyurea; HU) with 5FU. Drug cytotoxicity was observed by crystal violet staining assay. FdUMP was synthesized through the OPRT-RR pathway in SW48 cells but was scarcely synthesized through either the OPRT-RR or TP-TK pathway in SW48/5FUR cells. FdUMP amount in SW48/5FUR cells was reduced by 87% vs. SW48 cells. Expression levels of OPRT and TP were lower in SW48/5FUR when compared with these levels in the SW48 cells, indicating decreased synthesis of FdUMP-led 5FU resistance. These results indicated that fluoro-deoxyuridine (FdU) rather than 5FU promotes FdUMP synthesis and overcomes 5FU resistance. Contrastingly, FdUMP was synthesized through the OPRT-RR and TP-TK pathways in LS174T cells but mainly through the TP-TK pathway in LS174T/5FUR cells. FdUMP amount was similar in LS174T/5FUR vs. the LS174T cells. OPRT and RR expression was lower and TK expression was higher in LS174T/5FUR vs. the LS174T cells, indicating that dTMP synthesis increased through the salvage pathway, thus leading to 5FU resistance. LS174T/5FUR cells also showed cross-resistance to FdU and TS inhibitor, suggesting that nucleoside analogs such as trifluoro-thymidine should be used to overcome 5FU resistance in these cells. 5FU metabolism and mechanisms of 5FU resistance are different in each cell line. Both synthesized FdUMP amount and FdUMP sensitivity should be considered in 5FU-resistant cells.

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“…The activity of TK1 was examined in a study of colorectal cancer cell line HCT-116, which was knocked down for TK1 through CRISPR/Cas9 [ 27 ]. Compared with parental cells, cells without TK1 expression developed resistance to trifluridine/tipiracil.…”

Section: Biomarkers From Preclinical Modelsmentioning

confidence: 99%

“…Compared with parental cells, cells without TK1 expression developed resistance to trifluridine/tipiracil. In contrast, innate expression of TK1 in different colorectal cancer cell lines showed no correlation with trifluridine/tipiracil sensitivity, a fact that the authors attribute to different genetic backgrounds, which introduce additional and diverse molecular defects that could affect sensitivity [ 27 ]. Moreover, acquired resistance to trifluridine in the colorectal cancer cell line DLD1 is associated with loss of function of TK1 due to a point mutation in its gene, and resistance ensues in these cells through knockout of the gene through CRISPR/Cas9 [ 28 ].…”

Section: Biomarkers From Preclinical Modelsmentioning

confidence: 99%

Biomarkers of Trifluridine-Tipiracil Efficacy

Voutsadakis

2021

JCM

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Trifluridine/tipiracil (TAS-102) is a newer generation chemotherapy that has been approved for the later-line treatment of metastatic colorectal and gastric/gastroesophageal adenocarcinomas. The oral drug provides a modest benefit of prolongation of survival over placebo in pretreated patients with these cancers with acceptable toxicity. Studies have shown rare objective responses (2–4%), and the disease control rates were 44% in both colorectal and gastric cancer randomized trials. Thus, the majority of patients progress through treatment and are burdened by toxicities. To better characterize the sub-group of patients with a higher probability of benefit from trifluridine/tipiracil, predictive biomarkers have been sought using data from randomized trials as well as from non-randomized trials and real-world series. Biomarkers examined include clinical characteristics of the patients, laboratory tests, and tumor derived biomarkers. These studies show that early neutropenia on treatment, and ratios of leukocyte subsets, are potential biomarkers able to predict trifluridine/tipiracil benefit. Combinations of laboratory values and clinical characteristics and proteins involved in trifluridine transport and activation have been examined with initial positive results.

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Cytotoxicity of trifluridine correlates with the thymidine kinase 1 expression level

Cited by 16 publications

References 23 publications

Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets

Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets

Mechanism of acquired 5FU resistance and strategy for overcoming 5FU resistance focusing on 5FU metabolism in colon cancer cell lines

Biomarkers of Trifluridine-Tipiracil Efficacy

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