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

It is known that 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.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [2] ;  [6] ;  [7] ;  [8] ;  [9] ;  [10] ;  [11] ;  [12] more »; ORCiD logo [12] « less
  1. Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division
  2. Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Metabolomic Center and David Geffen School of Medicine
  3. Univ. of California, Los Angeles, CA (United States). Division of Hematology-Oncology
  4. Vector Pharma Advisors Inc., San Diego, CA (United States)
  5. Univ. of California, Los Angeles, CA (United States). Dept. of Microbiology, Immunology & Molecular Genetics
  6. Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Dept. of Psychiatry and Biobehavioral Sciences and Semel Inst. for Neuroscience and Human Behavior and Jonsson Comprehensive Cancer Center and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
  7. Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and David Geffen School of Medicine and Division of Hematology-Oncology and Jonsson Comprehensive Cancer Center and Dept. of Surgery and Dept. of Medicine-Division of Surgical Oncology
  8. Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division and David Geffen School of Medicine and Dept. of Biological Chemistry
  9. Univ. of California, Los Angeles, CA (United States). The Pasarow Mass Spectrometry Lab., Neuropsychiatric Institute-Semel Inst. for Neuroscience and Human Behavior
  10. Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division and The Pasarow Mass Spectrometry Lab., Neuropsychiatric Institute-Semel Inst. for Neuroscience and Human Behavior
  11. Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division and David Geffen School of Medicine and Dept. of Surgery
  12. Univ. of California, Los Angeles, CA (United States) Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division
Publication Date:
Grant/Contract Number:
SC0012353; R01 CA187678; P30 DK063491; R25 CA098010
Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Research Org:
Univ. of California, Los Angeles, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC); National Cancer Institute (NCI)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Acute lymphocytic leukaemia; DNA metabolism; DNA synthesis; Metabolomics
OSTI Identifier:
1425368