2. Academic Validation
  3. The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia

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

  • Nat Commun. 2017 Nov 22;8(1):1679. doi: 10.1038/s41467-017-01834-4.
Alessandro Di Tullio 1,  Kevin Rouault-Pierre 1 2,  Ander Abarrategi 1,  Syed Mian 1 3,  William Grey 1,  John Gribben 2,  Aengus Stewart 4,  Elizabeth Blackwood 5,  Dominique Bonnet 6
Affiliations

Affiliations

  • 1 Hematopoietic Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • 2 Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Chaterhouse Square, EC1M 6BQ, London, UK.
  • 3 King's College London School of Medicine, Department of Haematological Medicine, The Rayne Institute, 123 Coldharbour Lane, SE5 9NU, London, UK.
  • 4 Bioinformatic Core, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
  • 5 Genentech, 1 DNA Way, South San Francisco, CA, CA94 080, USA.
  • 6 Hematopoietic Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK. [email protected].
PMID: 29162833 DOI: 10.1038/s41467-017-01834-4
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.

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