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Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells

 Evan R Abt  ;  Thuc M Le  ;  Amanda M Dann  ;  Joseph R Capri  ;  Soumya Poddar  ;  Vincent Lok  ;  Luyi Li  ;  Keke Liang  ;  Amanda L Creech  ;  Khalid Rashid  ;  Woosuk Kim  ;  Nanping Wu  ;  Jing Cui  ;  Arthur Cho  ;  Hailey Rose Lee  ;  Ethan W Rosser  ;  Jason M Link  ;  Johannes Czernin  ;  Ting-Ting Wu  ;  Robert Damoiseaux  ;  David W Dawson  ;  Timothy R Donahue  ;  Caius G Radu 
 CELL REPORTS, Vol.38(2) : 110236, 2022-01 
Journal Title
Issue Date
Adenocarcinoma / metabolism ; Adenocarcinoma / pathology ; Animals ; Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins / metabolism ; Carcinoma, Pancreatic Ductal / metabolism* ; Carcinoma, Pancreatic Ductal / pathology ; Cell Cycle Checkpoints / drug effects ; Cell Line, Tumor ; DNA Damage / drug effects ; Female ; Humans ; Interferon Type I / metabolism* ; Interferon Type I / pharmacology ; Male ; Membrane Proteins / metabolism ; Mice ; Mice, Inbred NOD ; Nucleotides / antagonists & inhibitors ; Nucleotides / biosynthesis ; Nucleotides / metabolism ; Pancreatic Neoplasms / pathology ; Protein Kinase Inhibitors / pharmacology ; Signal Transduction / drug effects ; Xenograft Model Antitumor Assays
STING ; interferon ; nucleotide metabolism ; pancreas cancer ; replication stress
We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.
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1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
Yonsei Authors
Cho, Arthur Eung Hyuck(조응혁) ORCID logo https://orcid.org/0000-0001-8670-2473
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