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Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells.
Abt, Evan R; Le, Thuc M; Dann, Amanda M; Capri, Joseph R; Poddar, Soumya; Lok, Vincent; Li, Luyi; Liang, Keke; Creech, Amanda L; Rashid, Khalid; Kim, Woosuk; Wu, Nanping; Cui, Jing; Cho, Arthur; Lee, Hailey Rose; Rosser, Ethan W; Link, Jason M; Czernin, Johannes; Wu, Ting-Ting; Damoiseaux, Robert; Dawson, David W; Donahue, Timothy R; Radu, Caius G.
Afiliação
  • Abt ER; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Le TM; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Dann AM; Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
  • Capri JR; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Poddar S; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Lok V; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Li L; Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
  • Liang K; Department of General Surgery/Pancreatic and Thyroid Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
  • Creech AL; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Rashid K; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Kim W; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Wu N; Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
  • Cui J; Department of Pancreatic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
  • Cho A; Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • Lee HR; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Rosser EW; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Link JM; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
  • Czernin J; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA.
  • Wu TT; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
  • Damoiseaux R; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA; California NanoSystems Institute, University of California Los Angeles, Los Angeles, CA, USA;
  • Dawson DW; Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  • Donahue TR; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA; Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA; J
  • Radu CG; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angel
Cell Rep ; 38(2): 110236, 2022 01 11.
Article em En | MEDLINE | ID: mdl-35021095
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Interferon Tipo I / Carcinoma Ductal Pancreático Idioma: En Ano de publicação: 2022 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Interferon Tipo I / Carcinoma Ductal Pancreático Idioma: En Ano de publicação: 2022 Tipo de documento: Article