ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53 or ATM defective chronic lymphocytic leukemia cells

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@article{1fc6d74f55944c80a5dc67b8da71e0c7,
title = "ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53 or ATM defective chronic lymphocytic leukemia cells",
abstract = "TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53 or ATM defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53 or ATM defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis due to defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53 and ATM defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53 or ATM defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53 or ATM defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53 or ATM defective CLL that warrants clinical investigation.",
author = "Marwan Kwok and Nicholas Davies and Angelo Agathanggelou and Edward Smith and Ceri Oldreive and Eva Petermann and Grant Stewart and Jeff Brown and Alan Lau and Guy Pratt and Helen Parry and Malcolm Taylor and Paul Moss and Peter Hillmen and Tatjana Stankovic",
note = "Copyright {\textcopyright} 2015 American Society of Hematology.",
year = "2016",
month = feb,
day = "4",
doi = "10.1182/blood-2015-05-644872",
language = "English",
volume = "127",
pages = "582--595",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "5",

}

RIS

TY - JOUR

T1 - ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53 or ATM defective chronic lymphocytic leukemia cells

AU - Kwok, Marwan

AU - Davies, Nicholas

AU - Agathanggelou, Angelo

AU - Smith, Edward

AU - Oldreive, Ceri

AU - Petermann, Eva

AU - Stewart, Grant

AU - Brown, Jeff

AU - Lau, Alan

AU - Pratt, Guy

AU - Parry, Helen

AU - Taylor, Malcolm

AU - Moss, Paul

AU - Hillmen, Peter

AU - Stankovic, Tatjana

N1 - Copyright © 2015 American Society of Hematology.

PY - 2016/2/4

Y1 - 2016/2/4

N2 - TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53 or ATM defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53 or ATM defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis due to defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53 and ATM defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53 or ATM defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53 or ATM defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53 or ATM defective CLL that warrants clinical investigation.

AB - TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53 or ATM defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53 or ATM defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis due to defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53 and ATM defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53 or ATM defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53 or ATM defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53 or ATM defective CLL that warrants clinical investigation.

U2 - 10.1182/blood-2015-05-644872

DO - 10.1182/blood-2015-05-644872

M3 - Article

C2 - 26563132

VL - 127

SP - 582

EP - 595

JO - Blood

JF - Blood

SN - 0006-4971

IS - 5

ER -