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 DamoiseauxDavid W. Dawson, Timothy R. Donahue, Caius G. Radu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number110236
JournalCell Reports
Volume38
Issue number2
DOIs
StatePublished - Jan 11 2022
Externally publishedYes

Keywords

  • STING
  • interferon
  • nucleotide metabolism
  • pancreas cancer
  • replication stress

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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