Di Tullio, Alessandro, Rouault-Pierre, Kevin, Abarrategi, Ander et al. (6 more authors) (2017) The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukaemia. Nature Communications. 1679. ISSN 2041-1723
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.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © The Author(s) 2017 |
Dates: |
|
Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 14 Jan 2022 13:40 |
Last Modified: | 26 Nov 2024 00:52 |
Published Version: | https://doi.org/10.1038/s41467-017-01834-4 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s41467-017-01834-4 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:182566 |
Download
Filename: s41467_017_01834_4.pdf
Description: The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia
Licence: CC-BY 2.5