1. Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells
- Author
-
Abt, Evan R, Le, Thuc M, Dann, Amanda M, Capri, Joseph R, Poddar, Soumya, Lok, Vincent, Li, Luyi, Liang, Keke, Creech, Amanda L, Rashid, Khalid, Kim, Woosuk, Wu, Nanping, Cui, Jing, Cho, Arthur, Lee, Hailey Rose, Rosser, Ethan W, Link, Jason M, Czernin, Johannes, Wu, Ting-Ting, Damoiseaux, Robert, Dawson, David W, Donahue, Timothy R, and Radu, Caius G
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Cancer ,Digestive Diseases ,Pancreatic Cancer ,Rare Diseases ,Genetics ,Good Health and Well Being ,Adenocarcinoma ,Animals ,Ataxia Telangiectasia Mutated Proteins ,Carcinoma ,Pancreatic Ductal ,Cell Cycle Checkpoints ,Cell Line ,Tumor ,DNA Damage ,Female ,Humans ,Interferon Type I ,Male ,Membrane Proteins ,Mice ,Mice ,Inbred NOD ,Nucleotides ,Pancreatic Neoplasms ,Protein Kinase Inhibitors ,Signal Transduction ,Xenograft Model Antitumor Assays ,STING ,interferon ,nucleotide metabolism ,pancreas cancer ,replication stress ,Medical Physiology ,Biological sciences - Abstract
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.
- Published
- 2022