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

Evan R Abt; Thuc M Le; Amanda M Dann; Joseph R Capri; Soumya Poddar; Vincent Lok; Luyi Li; Keke Liang; Amanda L Creech; Khalid Rashid; Woosuk Kim; Nanping Wu; Jing Cui; Arthur Cho; Hailey Rose Lee; Ethan W Rosser; Jason M Link; Johannes Czernin; Ting-Ting Wu; Robert Damoiseaux; David W Dawson; Timothy R Donahue; Caius G Radu

doi:10.1016/j.celrep.2021.110236

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

Cell Rep. 2022 Jan 11;38(2):110236. doi: 10.1016/j.celrep.2021.110236.

Authors

Evan R Abt¹, Thuc M Le¹, Amanda M Dann², Joseph R Capri¹, Soumya Poddar¹, Vincent Lok¹, Luyi Li², Keke Liang³, Amanda L Creech¹, Khalid Rashid¹, Woosuk Kim¹, Nanping Wu², Jing Cui⁴, Arthur Cho⁵, Hailey Rose Lee¹, Ethan W Rosser¹, Jason M Link⁶, Johannes Czernin¹, Ting-Ting Wu⁷, Robert Damoiseaux⁸, David W Dawson⁹, Timothy R Donahue¹⁰, Caius G Radu¹¹

Affiliations

¹ 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.
² Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
³ Department of General Surgery/Pancreatic and Thyroid Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
⁴ Department of Pancreatic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
⁵ Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea.
⁶ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
⁷ Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.

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.

Publication types

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

MeSH terms

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

Substances

Interferon Type I
Membrane Proteins
Nucleotides
Protein Kinase Inhibitors
Sting1 protein, mouse
Atr protein, mouse
Ataxia Telangiectasia Mutated Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding