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Nat Commun. 2017 Aug 14;8(1):241. doi: 10.1038/s41467-017-00221-3.

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

Le TM1,2, Poddar S1,2, Capri JR1,2, Abt ER1,2, Kim W1,2, Wei L1,2, Uong NT1,2, Cheng CM1,2, Braas D1,3,4, Nikanjam M5, Rix P6, Merkurjev D7, Zaretsky J1,4, Kornblum HI1,8,9,10, Ribas A1,4,5,9,11,12, Herschman HR1,2,4,13, Whitelegge J14, Faull KF1,2,14, Donahue TR1,2,4,11, Czernin J1,2, Radu CG15,16.

Author information

1
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
2
Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
3
UCLA Metabolomic Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
4
David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
5
Division of Hematology-Oncology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
6
Vector Pharma Advisors Inc., San Diego, CA, 92130, USA.
7
Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
8
Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
9
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
10
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
11
Department of Surgery, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
12
Department of Medicine, Division of Surgical Oncology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
13
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
14
The Pasarow Mass Spectrometry Laboratory, Neuropsychiatric Institute-Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
15
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA. cradu@mednet.ucla.edu.
16
Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, CA, 90095, USA. cradu@mednet.ucla.edu.

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.

PMID:
28808226
PMCID:
PMC5556071
DOI:
10.1038/s41467-017-00221-3
[Indexed for MEDLINE]
Free PMC Article

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