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

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

Thuc M Le ¹ ², Soumya Poddar ¹ ², Joseph R Capri ¹ ², Evan R Abt ¹ ², Woosuk Kim ¹ ², Liu Wei ¹ ², Nhu T Uong ¹ ², Chloe M Cheng ¹ ², Daniel Braas ¹ ³ ⁴, Mina Nikanjam ⁵, Peter Rix ⁶, Daria Merkurjev ⁷, Jesse Zaretsky ¹ ⁴, Harley I Kornblum ¹ ⁸ ⁹ ¹⁰, Antoni Ribas ¹ ⁴ ⁵ ⁹ ¹¹ ¹², Harvey R Herschman ¹ ² ⁴ ¹³, Julian Whitelegge ¹⁴, Kym F Faull ¹ ² ¹⁴, Timothy R Donahue ¹ ² ⁴ ¹¹, Johannes Czernin ¹ ², Caius G Radu ¹⁵ ¹⁶

Affiliations

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.

PMID: 28808226 DOI: 10.1038/s41467-017-00221-3

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-16210

Forodesine

99.88%, PNP 抑制剂

Nucleoside Antimetabolite/Analog; Apoptosis

Cancer

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