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

Alessandro Di Tullio, Kevin Rouault-Pierre, Ander Abarrategi, Syed Mian, William Grey, John Gribben, Aengus Stewart, Elizabeth Blackwood and Dominique Bonnet ()
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Alessandro Di Tullio: The Francis Crick Institute
Kevin Rouault-Pierre: The Francis Crick Institute
Ander Abarrategi: The Francis Crick Institute
Syed Mian: The Francis Crick 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

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01834-4

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