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

Author

Listed:
  • Thuc M. Le

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Soumya Poddar

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Joseph R. Capri

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Evan R. Abt

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Woosuk Kim

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Liu Wei

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Nhu T. Uong

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Chloe M. Cheng

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Daniel Braas

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Mina Nikanjam

    (University of California, Los Angeles)

  • Peter Rix

    (Vector Pharma Advisors Inc.)

  • Daria Merkurjev

    (University of California, Los Angeles)

  • Jesse Zaretsky

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Harley I. Kornblum

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Antoni Ribas

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Harvey R. Herschman

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Julian Whitelegge

    (University of California, Los Angeles)

  • Kym F. Faull

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Timothy R. Donahue

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Johannes Czernin

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Caius G. Radu

    (University of California, Los Angeles
    University of California, Los Angeles)

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.

Suggested Citation

  • 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 & Peter Rix & Daria Merkurjev & Jesse Zaretsky & Harley , 2017. "ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00221-3
    DOI: 10.1038/s41467-017-00221-3
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    Cited by:

    1. Magali Saez-Ayala & Laurent Hoffer & Sébastien Abel & Khaoula Ben Yaala & Benoit Sicard & Guillaume P. Andrieu & Mehdi Latiri & Emma K. Davison & Marco A. Ciufolini & Paul Brémond & Etienne Rebuffet &, 2023. "From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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