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

Sarah E Fordham, Helen J Blair, Claire J Elstob, Ruth Plummer, Yvette Drew, Nicola J Curtin, Olaf Heidenreich, Deepali Pal, David Jamieson, Catherine Park, John Pollard, Scott Fields, Paul Milne, Graham H Jackson, Helen J Marr, Tobias Menne, Gail L Jones, James M Allan

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)
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Abstract

The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic 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 subunit, 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 hematologic malignancies.

Original languageEnglish
Pages (from-to)1157-1169
Number of pages13
JournalBlood
Volume2
Issue number10
Early online date22 May 2018
DOIs
Publication statusPublished - 22 May 2018

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