Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells.

Adenocarcinoma / metabolism Animals Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors Carcinoma, Pancreatic Ductal / metabolism Cell Cycle Checkpoints / drug effects Cell Line, Tumor DNA Damage / drug effects Female Humans Interferon Type I / metabolism Male Membrane Proteins / metabolism Mice Mice, Inbred NOD Nucleotides / antagonists & inhibitors Pancreatic Neoplasms / pathology Protein Kinase Inhibitors / pharmacology Signal Transduction / drug effects Xenograft Model Antitumor Assays Pancreatic Neoplasms
STING interferon nucleotide metabolism pancreas cancer replication stress

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
11 01 2022
Historique:
received: 02 07 2021
revised: 22 10 2021
accepted: 16 12 2021
entrez: 12 1 2022
pubmed: 13 1 2022
medline: 15 2 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2021.110236 PMID: 35021095 PMC: PMC8893345
pubmed: 35021095
pii: S2211-1247(21)01745-9
doi: 10.1016/j.celrep.2021.110236
pmc: PMC8893345
mid: NIHMS1771095
pii:
doi:

Substances chimiques

Interferon Type I 0
Membrane Proteins 0
Nucleotides 0
Protein Kinase Inhibitors 0
Sting1 protein, mouse 0
Atr protein, mouse EC 2.7.1.-
Ataxia Telangiectasia Mutated Proteins EC 2.7.11.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

110236

Subventions

Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009120
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA260678
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA211015
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA250529
Pays : United States

Informations de copyright

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests 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.

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Auteurs

Evan R 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.

Thuc M 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.

Amanda M Dann (AM)

Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.

Joseph R 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.

Soumya 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.

Vincent 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.

Luyi Li (L)

Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.

Keke Liang (K)

Department of General Surgery/Pancreatic and Thyroid Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Amanda L 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.

Khalid 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.

Woosuk 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.

Nanping Wu (N)

Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.

Jing Cui (J)

Department of Pancreatic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.

Arthur Cho (A)

Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea.

Hailey Rose 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.

Ethan W 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.

Jason M Link (JM)

Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.

Johannes 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.

Ting-Ting Wu (TT)

Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.

Robert 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; Department of Bioengineering, Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA, USA.

David W 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.

Timothy R 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; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: tdonahue@mednet.ucla.edu.

Caius G 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 Angeles, CA, USA. Electronic address: cradu@mednet.ucla.edu.

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Classifications MeSH

questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Eucaryotes › Animaux › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines liant le poly-adp-ribose › Protéines mutées dans l'ataxie-télangiectasie › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Carcinome du canal pancréatique › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Cycle cellulaire › Points de contrôle du cycle cellulaire › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interférons › Interféron de type I › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée NOD › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Reprogramming of nucleotide metabolism by...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Reprogramming of nucleotide metabolism by...