論文 - 詳細
| RRC ID | 66859 |
|---|---|
| 著者 | Ohashi S, Kikuchi O, Nakai Y, Ida T, Saito T, Kondo Y, Yamamoto Y, Mitani Y, Nguyen Vu TH, Fukuyama K, Tsukihara H, Suzuki N, Muto M. |
| タイトル | Synthetic Lethality with Trifluridine/Tipiracil and Checkpoint Kinase 1 Inhibitor for Esophageal Squamous Cell Carcinoma. |
| ジャーナル | Mol Cancer Ther |
| Abstract |
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. |
| 巻・号 | 19(6) |
| ページ | 1363-1372 |
| 公開日 | 2020-6-1 |
| DOI | 10.1158/1535-7163.MCT-19-0918 |
| PII | 1535-7163.MCT-19-0918 |
| PMID | 32371587 |
| MeSH | Animals Apoptosis Cell Proliferation Checkpoint Kinase 1 / antagonists & inhibitors* Checkpoint Kinase 1 / genetics Drug Combinations Esophageal Neoplasms / drug therapy Esophageal Neoplasms / genetics Esophageal Neoplasms / metabolism Esophageal Neoplasms / pathology* Esophageal Squamous Cell Carcinoma / drug therapy Esophageal Squamous Cell Carcinoma / genetics Esophageal Squamous Cell Carcinoma / metabolism Esophageal Squamous Cell Carcinoma / pathology* Humans Male Mice Mice, Hairless Mice, SCID Protein Kinase Inhibitors / pharmacology* Pyrrolidines / pharmacology* Synthetic Lethal Mutations* Thymine / pharmacology* Trifluridine / pharmacology* Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| IF | 5.615 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | TE-1(RCB1894) TE-10(RCB2099) TE-11(RCB2100) |