ATR inhibition amplifies antitumor effects of olaparib in biliary tract cancer. (28th September 2021)

• Record Type: Journal Article
• Authors: Nam, Ah-Rong; Yoon, Jeesun; Jin, Mei-Hua; Bang, Ju-Hee; Oh, Kyoung-Seok; Seo, Hye-Rim; Kim, Jae-Min; Kim, Tae-Yong; Oh, Do-Youn
• Is Part Of: Cancer letters. Volume 516(2021)
• Page Start: 38
• Page End: 47
• Publication Date: 2021-09-28
• Subjects: Biliary tract cancer -- DNA damage response -- PARP -- ATR -- PD-L1; ATM Ataxia telangiectasia mutated -- ATR Ataxia telangiectasia mutated and Rad3 -- BTC Biliary tract cancer -- CCL2 Chemokine (C–C motif) ligand 2 -- Chk1 Cell cycle checkpoint kinase 1 -- CI Combination index -- CXCL1 Chemokine (C-X-C motif) ligand 1 -- CtIP Carboxy-terminal binding protein-interacting protein -- DDR DNA damage response -- FOXA2 Forkhead box protein A2 -- HR Homologous recombination -- IC50 The half-maximal inhibitory concentration -- IL6 Interleukin-6 -- MTT 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide -- PARP poly-(ADP)-ribose polymerase -- PBMCs Human primary peripheral blood mononuclear cells -- p-STAT-3 Phosphorylation of signal transducer and activator of transcription 3 -- RECIST Response Evaluation Criteria in Solid Tumors -- TUNEL Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling -- YAP Yes-associated protein; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.05.029
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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.