UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Di Tullio, A; Rouault-Pierre, K; Abarrategi, A; Mian, S; Grey, W; Gribben, J; Stewart, A; ... Bonnet, D; + view all (2017) The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia. Nature Communications , 8 , Article 1679. 10.1038/s41467-017-01834-4. Green open access

[thumbnail of s41467-017-01834-4.pdf]
Preview
Text
s41467-017-01834-4.pdf - Published Version

Download (8MB) | Preview

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.

Type: Article
Title: The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-017-01834-4
Publisher version: http://doi.org/10.1038/s41467-017-01834-4
Language: English
Additional information: © The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10045554
Downloads since deposit
75Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item