Evidence map›Paper›PMID 28808226›Full record

ArticleNature communications2017

ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways.

Thuc M Le, Soumya Poddar, Joseph R Capri, Evan R Abt, Woosuk Kim, Liu Wei, Nhu T Uong, Chloe M Cheng, Daniel Braas, Mina Nikanjam and 11 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.

0numbers the graph read from it
0cells of the map it votes in
47citing papers in PubMed
2.7field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

47 citing papers in PubMed, 70 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. ATR kinase inhibitors induce mitochondrial fission in CD8bioRxiv : the preprint server for biology · 2026
    Article
  5. Conformationally gated multisite proton-coupled electron transfer in the ribonucleotide reductaseProceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  6. Article
  7. Article
  8. Article
  9. Article
  10. Review
  11. RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  12. Article
  13. Review
  14. Review
  15. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors at 2 institutions in 1 country.

Thuc M LeDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Soumya PoddarDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Joseph R CapriDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Evan R AbtDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Woosuk KimDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Liu WeiDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Nhu T UongDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Chloe M ChengDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Daniel BraasDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Mina NikanjamDivision of Hematology-Oncology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Peter RixVector Pharma Advisors Inc., San Diego, CA, 92130, USA.
Daria MerkurjevDepartment of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Jesse ZaretskyDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Harley I KornblumDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Antoni RibasDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Harvey R HerschmanDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Julian WhiteleggeThe Pasarow Mass Spectrometry Laboratory, Neuropsychiatric Institute-Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Kym F FaullDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Timothy R DonahueDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Johannes CzerninDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Caius G RaduDepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA. cradu@mednet.ucla.edu.ORCID http://orcid.org/0000-0002-9338-5397
University of California, Los Angeles · USVector Oncology (United States) · US

Funding

Transgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI PETER J TONTONOZ · 2003 to 2026
$40.4M
UCLA-Caltech Medical Scientist Training ProgramT32GM008042 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI AJIJOLA, OLUJIMI A, DAWSON, DAVID WAYNE · 1985 to 2023
$29.9M
UCLA SPORE in Brain CancerP50CA211015 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI David A. Nathanson · 2017 to 2026
$25.2M
UCLA Scholars in Oncologic Molecular lmaging (SOMI)R25CA098010 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI PHELPS, MICHAEL E · 2003 to 2013
$5.0M
PET Imaging-guided Personalized Therapy in Pancreatic CancerR01CA187678 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CZERNIN, JOHANNES, DONAHUE, TIMOTHY R · 2014 to 2018
$2.8M
NCI NIH HHS P50 CA211015NCI NIH HHS R01 CA187678NCI NIH HHS R25 CA098010NIDDK NIH HHS P30 DK063491
6 · The paper itself

Abstract

Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms. Quantification of nucleotide biosynthesis in ATR-inhibited acute lymphoblastic leukemia (ALL) cells reveals substantial remaining de novo and salvage activities, and could not eliminate the disease in vivo. However, targeting these remaining activities with RNR and dCK inhibitors triggers lethal replication stress in vitro and long-term disease-free survival in mice with B-ALL, without detectable toxicity. Thus the functional interplay between alternative nucleotide biosynthetic routes and ATR provides therapeutic opportunities in leukemia and potentially other cancers.Leukemic cells depend on the nucleotide synthesis pathway to proliferate. Here the authors use metabolomics and proteomics to show that inhibition of ATR reduced the activity of these pathways thus providing a valuable therapeutic target in leukemia.

Indexed as

AnimalsAtaxia Telangiectasia Mutated ProteinsBiosynthetic PathwaysDeoxycytidine KinaseDNA ReplicationFemaleHumansMiceMice, Inbred C57BLNucleotidesPrecursor Cell Lymphoblastic Leukemia-LymphomaRibonucleotide ReductasesAtaxia Telangiectasia Mutated ProteinsDeoxycytidine KinaseNucleotidesRibonucleotide Reductases

Identifiers

PMID28808226
PMCPMC5556071
OpenAlexW2743992255

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.