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The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia

Author

Listed:
  • Alessandro Di Tullio

    (The Francis Crick Institute)

  • Kevin Rouault-Pierre

    (The Francis Crick Institute
    Barts Cancer Institute, Queen Mary University of London, Chaterhouse Square)

  • Ander Abarrategi

    (The Francis Crick Institute)

  • Syed Mian

    (The Francis Crick Institute
    Department of Haematological Medicine, The Rayne Institute)

  • William Grey

    (The Francis Crick Institute)

  • John Gribben

    (Barts Cancer Institute, Queen Mary University of London, Chaterhouse Square)

  • Aengus Stewart

    (The Francis Crick Institute)

  • Elizabeth Blackwood

    (Genentech, 1 DNA Way)

  • Dominique Bonnet

    (The Francis Crick Institute)

Abstract

Cytarabine (AraC) represents the most effective single agent treatment for AML. Nevertheless, overriding AraC resistance in AML remains an unmet medical need. Here we show that the CHK1 inhibitor (CHK1i) GDC-0575 enhances AraC-mediated killing of AML cells both in vitro and in vivo, thus abrogating any potential chemoresistance mechanisms involving DNA repair. Importantly, this combination of drugs does not affect normal long-term hematopoietic stem/progenitors. Moreover, the addition of CHK1i to AraC does not generate de novo mutations and in patients’ samples where AraC is mutagenic, addition of CHK1i appears to eliminate the generation of mutant clones. Finally, we observe that persistent residual leukemic cells are quiescent and can become responsive to the treatment when forced into cycle via granulocyte colony-stimulating factor (G-CSF) administration. This drug combination (AraC+CHK1i+G-CSF) will open the doors for a more efficient treatment of AML in the clinic.

Suggested Citation

  • Alessandro Di Tullio & Kevin Rouault-Pierre & Ander Abarrategi & Syed Mian & William Grey & John Gribben & Aengus Stewart & Elizabeth Blackwood & Dominique Bonnet, 2017. "The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01834-4
    DOI: 10.1038/s41467-017-01834-4
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    Cited by:

    1. Limei Wu & Srinivas Chatla & Qiqi Lin & Fabliha Ahmed Chowdhury & Werner Geldenhuys & Wei Du, 2021. "Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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