論文 - 詳細
| RRC ID | 63795 |
|---|---|
| 著者 | Nam AR, Jin MH, Bang JH, Oh KS, Seo HR, Oh DY, Bang YJ. |
| タイトル | Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer. |
| ジャーナル | Cancer Res Treat |
| Abstract |
PURPOSE:Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC. Materials and Methods:In this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models. RESULTS:AZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy. CONCLUSION:Taken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC. |
| 巻・号 | 52(3) |
| ページ | 945-956 |
| 公開日 | 2020-7-1 |
| DOI | 10.4143/crt.2020.080 |
| PII | crt.2020.080 |
| PMID | 32311864 |
| PMC | PMC7373879 |
| MeSH | Animals Apoptosis Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors* Ataxia Telangiectasia Mutated Proteins / genetics Ataxia Telangiectasia Mutated Proteins / metabolism Biliary Tract Neoplasms / drug therapy* Biliary Tract Neoplasms / metabolism Biliary Tract Neoplasms / pathology Cell Cycle Cell Cycle Proteins / antagonists & inhibitors* Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Cell Movement Cell Proliferation Drug Resistance, Neoplasm* Female Gene Expression Regulation, Neoplastic / drug effects* Humans Indoles Mice Mice, Nude Middle Aged Morpholines Prognosis Protein-Tyrosine Kinases / antagonists & inhibitors* Protein-Tyrosine Kinases / genetics Protein-Tyrosine Kinases / metabolism Pyrimidines / pharmacology* Sulfonamides Sulfoxides / pharmacology* Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| IF | 3.761 |
| リソース情報 | |
| ヒト・動物細胞 | HuCCT1(RCB1960) TFK-1(RCB2537) |