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 because of 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.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom;
authors.forename: Marwan
authors.initials: M
authors.lastname: Kwok
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Davies
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Angelo
authors.initials: A
authors.lastname: Agathanggelou
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Edward
authors.initials: E
authors.lastname: Smith
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Ceri
authors.initials: C
authors.lastname: Oldreive
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Eva
authors.initials: E
authors.lastname: Petermann
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Grant
authors.initials: G
authors.lastname: Stewart
authors.affiliation: Oncology iMed, AstraZeneca Pharmaceuticals, Waltham, MA;
authors.forename: Jeff
authors.initials: J
authors.lastname: Brown
authors.affiliation: R&D Oncology iMed, AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom;
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; Birmingham Heartlands Hospital, Birmingham, United Kingdom; and.
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom;
authors.forename: Helen
authors.initials: H
authors.lastname: Parry
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Malcolm
authors.initials: M
authors.lastname: Taylor
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom;
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom;
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C551803:ibrutinib; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000225:Adenine