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

Fordham, Sarah E., Blair, Helen J., Elstob, Claire J., Plummer, Ruth, Drew, Yvette, Curtin, Nicola J., Heidenreich, Olaf, Pal, Deepali, Jamieson, David, Park, Catherine, Pollard, John, Fields, Scott, Milne, Paul, Jackson, Graham H., Marr, Helen J., Menne, Tobias, Jones, Gail L. and Allan, James M. (2018) Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase. Blood Advances, 2 (10). pp. 1157-1169. ISSN 2473-9529

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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.

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