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Lookup NU author(s): Dr Sarah FordhamORCiD, Dr Helen Blair, Dr Claire Elstob, Professor Ruth Plummer, Dr Yvette DrewORCiD, Professor Nicola CurtinORCiD, Professor Olaf Heidenreich, Dr Deepali Pal, Dr David Jamieson, Dr Catherine Park, Dr Paul Milne, Professor Graham Jackson, Dr Helen Marr, Dr Tobias Menne, Dr Gail Jones, Professor James Allan
This is the final published version of an article that has been published in its final definitive form by American Society of Hematology, 2018.
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The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signalling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the anti-leukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition, via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR sub-unit, the ATR inhibitor VX-970 eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other haematological malignancies.
Author(s): Fordham SE, Blair HJ, Elstob CJ, Plummer R, Drew Y, Curtin NJ, Heidenreich O, Pal D, Jamieson D, Park C, Pollard J, Fields S, Milne P, Jackson GH, Marr HJ, Menne T, Jones GJ, Allan JM
Publication type: Article
Publication status: Published
Journal: Blood Advances
Year: 2018
Volume: 2
Issue: 10
Pages: 1157-1169
Online publication date: 22/05/2018
Acceptance date: 09/04/2018
Date deposited: 05/06/2018
Publisher: American Society of Hematology
URL: https://doi.org/10.1182/bloodadvances.2017015214
DOI: 10.1182/bloodadvances.2017015214
PubMed id: 29789314
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