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Inhibition of ATR acutely sensitises acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase

Lookup NU author(s): Dr Sarah Fordham, Dr Helen Blair, Dr Claire Elstob, Professor Ruth Plummer, Dr Yvette Drew, Professor Nicola Curtin, 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

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This is the final published version of an article that has been published in its final definitive form by American Society of Hematology, 2018.

For re-use rights please refer to the publisher's terms and conditions.


Abstract

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.


Publication metadata

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

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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