The Replication Stress Response Kinase ATR is an Interferon Signaling Driven Co-Dependency In Pancreas Cancer Cells

Abstract

An inflammatory, cytokine-rich tumor microenvironment is a defining feature of pancreatic ductal adenocarcinoma (PDAC). Among proinflammatory cytokines, type I interferons (IFNs) are particularly important as they regulate the expression of hundreds of genes. It is however unclear whether IFN signaling in PDAC tumors can be leveraged therapeutically. We determined that a type I IFN response transcriptional signature is enriched in a subset of PDAC and that IFN signaling biomarkers are detectable in patient-derived and cell line xenograft tumors. To systematically identify actionable vulnerabilities induced by IFN, we integrated a mass spectrometry-based phosphoproteomic analysis and a chemical genomics high-throughput synthetic lethality screen which together revealed that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) and sensitizes tumor cells to ATR inhibitors. In vitro, IFNs induce replication stress and cell cycle arrest in S-phase which is accompanied by nucleotide pool insufficiency and enhanced nucleoside efflux into the extracellular environment. In combination with IFN, ATR inhibitors induce lethal DNA damage, downregulate de novo nucleotide biosynthesis mediated by ribonucleotide reductase, and deplete nucleotide pools. In vivo, ATR inhibitors limit the growth of subcutaneous and orthotopic PDAC tumors in which IFN production is driven by the activation of stimulator of interferon genes (STING). These results highlight critical crosstalk between IFN signaling, the DNA replication stress response network, and nucleotide metabolism in PDAC while providing the rationale for exploring targeted therapeutic interventions that leverage the tumor cell autonomous effects of IFN signaling.