dc.contributor.author | Di Tullio, A | en_US |
dc.contributor.author | Rouault-Pierre, K | en_US |
dc.contributor.author | Abarrategi, A | en_US |
dc.contributor.author | Mian, S | en_US |
dc.contributor.author | Grey, W | en_US |
dc.contributor.author | Gribben, J | en_US |
dc.contributor.author | Stewart, A | en_US |
dc.contributor.author | Blackwood, E | en_US |
dc.contributor.author | Bonnet, D | en_US |
dc.date.accessioned | 2018-03-07T12:11:25Z | |
dc.date.available | 2017-10-19 | en_US |
dc.date.issued | 2017-11-22 | en_US |
dc.date.submitted | 2018-02-22T15:00:35.679Z | |
dc.identifier.other | 10.1038/s41467-017-01834-4 | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/34404 | |
dc.description.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. | en_US |
dc.description.sponsorship | This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010045), the UK Medical Research Council (FC0010045), and the Wellcome Trust (FC001045), and by Genentech (research grant to D.B.). | en_US |
dc.format.extent | 1679 - ? | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Nat Commun | en_US |
dc.rights | Creative Commons Attribution License | |
dc.subject | Animals | en_US |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | en_US |
dc.subject | Cell Line, Tumor | en_US |
dc.subject | Checkpoint Kinase 1 | en_US |
dc.subject | Cytarabine | en_US |
dc.subject | Drug Resistance, Neoplasm | en_US |
dc.subject | Female | en_US |
dc.subject | Granulocyte Colony-Stimulating Factor | en_US |
dc.subject | HL-60 Cells | en_US |
dc.subject | Hematopoiesis | en_US |
dc.subject | Humans | en_US |
dc.subject | Leukemia, Myeloid, Acute | en_US |
dc.subject | Male | en_US |
dc.subject | Mice | en_US |
dc.subject | Mice, Inbred NOD | en_US |
dc.subject | Mice, SCID | en_US |
dc.subject | Mutation | en_US |
dc.subject | Piperidines | en_US |
dc.subject | Protein Kinase Inhibitors | en_US |
dc.subject | Pyridines | en_US |
dc.subject | Pyrroles | en_US |
dc.subject | U937 Cells | en_US |
dc.subject | Xenograft Model Antitumor Assays | en_US |
dc.title | The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia. | en_US |
dc.type | Article | |
dc.rights.holder | 2017. The authors | |
dc.identifier.doi | 10.1038/s41467-017-01834-4 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/29162833 | en_US |
pubs.issue | 1 | en_US |
pubs.notes | No embargo | en_US |
pubs.publication-status | Published online | en_US |
pubs.volume | 8 | en_US |
dcterms.dateAccepted | 2017-10-19 | en_US |