論文 - 詳細
| RRC ID | 69792 |
|---|---|
| 著者 | Seo HR, Nam AR, Bang JH, Oh KS, Kim JM, Yoon J, Kim TY, Oh DY. |
| タイトル | Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer. |
| ジャーナル | Cancer Res Treat |
| Abstract |
Purpose:Up to 20% of patients with biliary tract cancer (BTC) have alterations in DNA damage response (DDR) genes, including homologous recombination (HR) genes. Therefore, the DDR pathway could be a promising target for new drug development in BTC. We aim to investigate the anti-tumor effects using PARP and WEE1 inhibitors in BTC. Materials and Methods:We used 10 biliary tract cancer cell lines to evaluate an anti-tumor effect of olaparib (a PARP inhibitor) and AZD1775 (a WEE1 inhibitor) in in vitro. Additionally, we established SNU869 xenograft model for in vivo experiments. Results:In this study, we observed a modest anti-proliferative effect of olaparib. DNA double-strand break (DSB) and apoptosis were increased by olaparib in BTC cells. However, olaparib-induced DNA DSB was repaired through the HR pathway, and G2 arrest was induced to secure the time for repair. As AZD1775 typically regulates the G2/M checkpoint, we combined olaparib with AZD1775 to abrogate G2 arrest. We observed that AZD1775 downregulated p-CDK1, a G2/M cell cycle checkpoint protein, and induced early mitotic entry. AZD1775 also decreased CtIP and RAD51 expression and disrupted HR repair. In xenograft model, olaparib plus AZD1775 treatment reduced tumor growth more potently than did monotherapy with either drug. Conclusion:This is the first study to suggest that olaparib combined with AZD1775 can induce synergistic anti-tumor effects against BTC. Combination therapy that blocks dual PARP and WEE1 has the potential to be further clinically developed for BTC patients. |
| 巻・号 | 54(2) |
| ページ | 541-553 |
| 公開日 | 2022-4-1 |
| DOI | 10.4143/crt.2021.473 |
| PII | crt.2021.473 |
| PMID | 34352995 |
| PMC | PMC9016294 |
| MeSH | Antineoplastic Agents* / therapeutic use Apoptosis Biliary Tract Neoplasms* / drug therapy Biliary Tract Neoplasms* / genetics Biliary Tract Neoplasms* / metabolism Cell Cycle Proteins Cell Line, Tumor Cell Proliferation DNA Humans Poly(ADP-ribose) Polymerase Inhibitors / pharmacology Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use Protein-Tyrosine Kinases Xenograft Model Antitumor Assays |
| IF | 3.761 |
| リソース情報 | |
| ヒト・動物細胞 | HuCCT1(RCB1960) TFK-1(RCB2537) |