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

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 chemothera...

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Bibliographic Details
Published in:Blood advances 2018-05, Vol.2 (10), p.1157-1169
Main Authors: 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., Allan, James M.
Format: Article
Language:English
Subjects:
Aged
Animals
Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors
Cell Line
Disease Models, Animal
Female
Humans
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - metabolism
Mice
Middle Aged
Myeloid Neoplasia
Nucleosides - metabolism
Ribonucleotide Reductases - genetics
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Summary: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. •Loss of ATR signaling is cytotoxic to AML cells in combination with gemcitabine and hydroxyurea via the induction of replication stress.•A small molecule inhibitor of ATR in combination with gemcitabine completely eradicates AML in an orthotopic xenograft mouse model. [Display omitted]
ISSN:2473-9529
2473-9537
DOI:10.1182/bloodadvances.2017015214