title: The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo.
abstract: ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Vendetti
authors.affiliation: Cancer Bioscience, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schamus
authors.affiliation: Women's Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Conrads
authors.affiliation: Cancer Bioscience, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bakkenist
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001682:Biological Availability; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007211:Indoles; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008819:Mice, Nude; D009025:Morpholines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D034622:RNA Interference; D013449:Sulfonamides; D013454:Sulfoxides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D007211:Indoles; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013454:Sulfoxides; D003841:Deoxycytidine; C000611951:ceralasertib; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D002945:Cisplatin; D000093542:Gemcitabine
keywords: ATM and Rad-3-related (ATR); DNA damage response; ataxia telangiectasia mutated (ATM); cisplatin; non-small cell lung cancer (NSCLC)