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

doi:10.1182/bloodadvances.2017015214

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

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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 language	English
Pages (from-to)	1157-1169
Number of pages	13
Journal	Blood
Volume	2
Issue number	10
Early online date	22 May 2018
DOIs	https://doi.org/10.1182/bloodadvances.2017015214
Publication status	Published - 22 May 2018

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Fordham, S. E., Blair, H. J., Elstob, C. J., Plummer, R., Drew, Y., Curtin, N. J., Heidenreich, O., Pal, D., Jamieson, D., Park, C., Pollard, J., Fields, S., Milne, P., Jackson, G. H., Marr, H. J., Menne, T., Jones, G. L., & Allan, J. M. (2018). Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase. Blood, 2(10), 1157-1169. https://doi.org/10.1182/bloodadvances.2017015214

@article{d5089c8a3c5e4286b6fca4e635117df7,

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

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.",

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

note = "{\textcopyright} 2018 by The American Society of Hematology.",

year = "2018",

month = may,

day = "22",

doi = "10.1182/bloodadvances.2017015214",

language = "English",

volume = "2",

pages = "1157--1169",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "10",

}

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, GL & Allan, JM 2018, 'Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase', Blood, vol. 2, no. 10, pp. 1157-1169. https://doi.org/10.1182/bloodadvances.2017015214

TY - JOUR

T1 - Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase

AU - Fordham, Sarah E

AU - Blair, Helen J

AU - Elstob, Claire J

AU - Plummer, Ruth

AU - Drew, Yvette

AU - Curtin, Nicola J

AU - Heidenreich, Olaf

AU - Pal, Deepali

AU - Jamieson, David

AU - Park, Catherine

AU - Pollard, John

AU - Fields, Scott

AU - Milne, Paul

AU - Jackson, Graham H

AU - Marr, Helen J

AU - Menne, Tobias

AU - Jones, Gail L

AU - Allan, James M

PY - 2018/5/22

Y1 - 2018/5/22

N2 - 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.

AB - 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.

U2 - 10.1182/bloodadvances.2017015214

DO - 10.1182/bloodadvances.2017015214

M3 - Article

C2 - 29789314

SN - 0006-4971

VL - 2

SP - 1157

EP - 1169

JO - Blood

JF - Blood

IS - 10

ER -

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

Abstract

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