Journal
CELL REPORTS
Volume 38, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.110236
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Funding
- NIH [R01 1R01CA250529-01A1]
- UCLA Tumor Immunology Training Grant [T32CA009120]
- Hirshberg Foundation
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Type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors. IFN activates the ATR kinase, leading to cell-cycle arrest in S-phase, nucleotide pool insufficiency, and nucleoside efflux in PDAC cells. ATR inhibitors, combined with IFN, induce lethal DNA damage and downregulate nucleotide biosynthesis. This study reveals the interaction between IFN, DNA replication stress response networks, and nucleotide metabolism, providing a rationale for targeted therapeutic interventions leveraging IFN signaling in tumors.
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 PDACtumors 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 nucleotidemetabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.
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