Cancer Res Treat.  2019 Jul;51(3):1167-1179. 10.4143/crt.2018.526.

Therapeutic Targeting of the DNA Damage Response Using an ATR Inhibitor in Biliary Tract Cancer

Affiliations
  • 1Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. ohdoyoun@snu.ac.kr
  • 2Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Abstract

PURPOSE
The DNA damage response (DDR) is a multi-complex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints, and apoptosis. In the case of biliary tract cancer (BTC), the strategy of DDR targeting has not been evaluated, even though many patients have DNA repair pathway alterations. The purpose of this study was to test the DDR-targeting strategy in BTC using an ataxia-telangiectasia and Rad3-related (ATR) inhibitor.
MATERIALS AND METHODS
A total of nine human BTC cell lines were used for evaluating anti-tumor effect of AZD6738 (ATR inhibitor) alone or combination with cytotoxic chemotherapeutic agents through MTT assay, colony-forming assays, cell cycle analyses, and comet assays. We established SNU478-mouse model for in vivo experiments to confirm our findings.
RESULTS
Among nine human BTC cell lines, SNU478 and SNU869 were the most sensitive to AZD6738, and showed low expression of both ataxia-telangiectasia mutated (ATM) and p53. AZD6738 blocked p-Chk1 and p-glycoprotein and increased γH2AX, a marker of DNA damage, in sensitive cells. AZD6738 significantly increased apoptosis, G2/M arrest and p21, and decreased CDC2. Combinations of AZD6738 and cytotoxic chemotherapeutic agents exerted synergistic effects in colony-forming assays, cell cycle analyses, and comet assays. In our mouse models, AZD6738 monotherapy decreased tumor growth and the combination with cisplatin showed more potent effects on growth inhibition, decreased Ki-67, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling than monotherapy with each drug.
CONCLUSION
In BTC, DDR targeting strategy using ATR inhibitor demonstrated promising antitumor activity alone or in combination with cytotoxic chemotherapeutic agents. This supports further clinical development of DDR targeting strategy in BTC.

Keyword

DNA damage response; ATR inhibitor; Biliary tract neoplasms; ATM; p53

MeSH Terms

Animals
Apoptosis
Ataxia Telangiectasia
Biliary Tract Neoplasms*
Biliary Tract*
Cell Cycle
Cell Cycle Checkpoints
Cell Line
Cisplatin
Comet Assay
DNA Damage*
DNA Repair
DNA*
Humans
Mice
P-Glycoprotein
Cisplatin
DNA
P-Glycoprotein
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