Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer
Autor: | Yung-Jue Bang, Do-Youn Oh, Hye-Rim Seo, Ah-Rong Nam, Ju-Hee Bang, Meihua Jin, Kyoung-Seok Oh |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research Indoles DNA damage Morpholines Mice Nude Apoptosis Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins DNA damage response 03 medical and health sciences Mice 0302 clinical medicine In vivo Cell Movement Tumor Cells Cultured Medicine Animals Humans MTT assay WEE1 Cell Proliferation Sulfonamides Migration Assay business.industry Cell Cycle Middle Aged Protein-Tyrosine Kinases Prognosis Xenograft Model Antitumor Assays In vitro Comet assay Gene Expression Regulation Neoplastic 030104 developmental biology ATR Biliary Tract Neoplasms Pyrimidines Oncology Cell culture Drug Resistance Neoplasm 030220 oncology & carcinogenesis Sulfoxides Cancer research Original Article Female business |
Zdroj: | Cancer Research and Treatment : Official Journal of Korean Cancer Association |
ISSN: | 2005-9256 1598-2998 |
Popis: | PurposeCurrently, 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 MethodsIn 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.ResultsAZD1775 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.ConclusionTaken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC. |
Databáze: | OpenAIRE |
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