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

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 38 Issue 2 Pg. 110236 (01 11 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35021095 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Interferon Type I
• Membrane Proteins
• Nucleotides
• Protein Kinase Inhibitors
• Sting1 protein, mouse
• Atr protein, mouse
• Ataxia Telangiectasia Mutated Proteins

Topics

• Adenocarcinoma (metabolism, pathology)
• Animals
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, metabolism)
• Carcinoma, Pancreatic Ductal (metabolism, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• DNA Damage (drug effects)
• Female
• Humans
• Interferon Type I (metabolism, pharmacology)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred NOD
• Nucleotides (antagonists & inhibitors, biosynthesis, metabolism)
• Pancreatic Neoplasms (pathology)
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays
• Pancreatic Neoplasms