ATR inhibition amplifies antitumor effects of olaparib in biliary tract cancer
| Autor: | Kyoung Seok Oh, Hye Rim Seo, Jae-Min Kim, Ah Rong Nam, Tae Yong Kim, Ju Hee Bang, Mei Hua Jin, Do Youn Oh, Jeesun Yoon |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research DNA damage Poly ADP ribose polymerase Down-Regulation Mice Nude Antineoplastic Agents Ataxia Telangiectasia Mutated Proteins Poly(ADP-ribose) Polymerase Inhibitors CXCR4 Peripheral blood mononuclear cell Piperazines Olaparib Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor PD-L1 Animals Humans Medicine Protein Kinase Inhibitors Cells Cultured Cell Proliferation biology business.industry Xenograft Model Antitumor Assays In vitro Biliary Tract Neoplasms 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis PARP inhibitor Leukocytes Mononuclear biology.protein Cancer research Phthalazines Female business |
| Zdroj: | Cancer Letters. 516:38-47 |
| ISSN: | 0304-3835 |
| Popis: | Olaparib, a potent PARP inhibitor, has been shown to have great anti-tumor effects in some tumor types. Although biliary tract cancer (BTC) is a good candidate for DNA damage response (DDR)-targeted agents, targeted DDR inhibitors, including olaparib, are currently rarely evaluated in BTC. In our project, a total of ten BTC cell lines were used to assess the efficacy of olaparib. Olaparib alone showed moderate anti-proliferative effects in BTC cells and increased p-ATR and PD-L1 expression levels. In combination with an ATR inhibitor (AZD6738, ceralasertib) showed synergistic anti-proliferative effects and increased DNA strand breaks in vitro. PD-L1 induced by olaparib was also downregulated by ceralasertib through p-STAT-3 and YAP reduction with or without human primary peripheral blood mononuclear cells. In SNU478-xenograft models, the combination treatment significantly suppressed tumor growth. PD-L1 and YAP were strongly downregulated, similar to in vitro conditions, and expression of CXCR2 and CXCR4 was further reduced. In the current ongoing clinical trial (NCT04298021), BTC patients treated with olaparib and ceralasertib combination have shown tumor response. In conclusion, co-targeting of PARP and ATR might be a potential therapeutic approach for patients with BTC. |
| Databáze: | OpenAIRE |
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