@article{06e84343cc7e4de8995a267d11c66b00,
title = "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.",
keywords = "STING, interferon, nucleotide metabolism, pancreas cancer, replication stress",
author = "Abt, {Evan R.} and Le, {Thuc M.} and Dann, {Amanda M.} and Capri, {Joseph R.} and Soumya Poddar and Vincent Lok and Luyi Li and Keke Liang and Creech, {Amanda L.} and Khalid Rashid and Woosuk Kim and Nanping Wu and Jing Cui and Arthur Cho and Lee, {Hailey Rose} and Rosser, {Ethan W.} and Link, {Jason M.} and Johannes Czernin and Wu, {Ting Ting} and Robert Damoiseaux and Dawson, {David W.} and Donahue, {Timothy R.} and Radu, {Caius G.}",
note = "Funding Information: We thank Joel Almajano, Kyle Current, and Firas Hikmat for assistance performing animal studies. We thank Chloe M. Cheng, Juna Yi, Suhasini Gupta, Aiden Hsu, Joanna Li, and Janet Song for outstanding technical assistance. We thank Michael Y. Wang for reviewing the manuscript. We thank Bobby Tofig and Constance Yuen at the UCLA Molecular Shared Screening Resource for assistance in performing the high-throughput screen. This work was supported by NIH R01 1R01CA250529-01A1. E.R.A. is supported by UCLA Tumor Immunology Training Grant T32CA009120. T.M.L. is supported by the Hirshberg Foundation Seed Grant. Conception and design, E.R.A. T.M.L. A.M.D. T.R.D. and C.G.R.; development of methodology, E.R.A. T.M.L. A.M.D. J.R.C. T.-T.W. J. Czernin, R.D. and D.W.D.; acquisition of data, E.R.A. T.M.L. A.M.D. J.R.C. K.L. N.W. H.R.L. L.L. S.P. W.K. V.L. K.R. A.L.C. and J.M.L.; IHC analysis, A.M.D. N.W. and K.L.; MS data acquisition and analysis, T.M.L. and J.R.C.; development of cell line models, L.L.; animal studies, J. Cui and A.C.; analysis and interpretation of data: E.R.A. T.M.L. A.M.D. T.R.D. and C.G.R.; writing, review, and/or revision of the manuscript, E.R.A. D.W.D. T.R.D. and C.G.R.; study supervision, T.R.D. and C.G.R. C.G.R. and J. Czernin are co-founders of Sofie Biosciences and Trethera Corporation. They and the University of California (UC) hold equity in Sofie Biosciences and Trethera Corporation. T.R.D. is an executive board member and holds equity in Trethera Corporation. The intellectual property developed by C.G.R. and J. Czernin and licensed by UC to Sofie Biosciences and Trethera Corporation was not used in this study. Funding Information: We thank Joel Almajano, Kyle Current, and Firas Hikmat for assistance performing animal studies. We thank Chloe M. Cheng, Juna Yi, Suhasini Gupta, Aiden Hsu, Joanna Li, and Janet Song for outstanding technical assistance. We thank Michael Y. Wang for reviewing the manuscript. We thank Bobby Tofig and Constance Yuen at the UCLA Molecular Shared Screening Resource for assistance in performing the high-throughput screen. This work was supported by NIH R01 1R01CA250529-01A1 . E.R.A. is supported by UCLA Tumor Immunology Training Grant T32CA009120 . T.M.L. is supported by the Hirshberg Foundation Seed Grant. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2022",
month = jan,
day = "11",
doi = "10.1016/j.celrep.2021.110236",
language = "English (US)",
volume = "38",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}