title: Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei.
abstract: AZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found in vitro growth inhibitory activity of this ATRi in a panel of human cancer cell lines. We demonstrated radiosensitization by AZD6738 to single radiation fractions in multiple cancer cell lines independent of both p53 and BRCA2 status by the clonogenic assay. Radiosensitization by AZD6738 to clinically relevant doses of fractionated radiation was demonstrated in vitro using a 3D tumor spheroid model and, in vivo, AZD6738 radiosensitized by abrogating the radiation-induced G2cell-cycle checkpoint and inhibiting homologous recombination. Mitosis with damaged DNA resulted in mitotic catastrophe as measured by micronucleus formation by live-cell fluorescent-ubiquitination cell-cycle imaging of cell-cycle progression and nuclear morphology. Induction of micronuclei was significantly more prominent for AZD6738 compared with inhibition of the downstream kinase CHK1 alone at isoeffective doses. Micronuclei were characterized as acentric chromosomal fragments, which displayed characteristics of increased DNA damage and cell-cycle dyssynchrony when compared with the primary nucleus. Mol Cancer Ther; 16(1); 25-34. ©2016 AACR.
authors.affiliation: Targeted Therapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
authors.forename: Magnus T
authors.initials: MT
authors.lastname: Dillon
authors.affiliation: Targeted Therapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Barker
authors.affiliation: Targeted Therapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
authors.forename: Malin
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: Targeted Therapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
authors.forename: Hind
authors.initials: H
authors.lastname: Hafsi
authors.affiliation: The Royal Marsden Hospital, London, UK.
authors.forename: Shreerang A
authors.initials: SA
authors.lastname: Bhide
authors.affiliation: The Royal Marsden Hospital, London, UK.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Newbold
authors.affiliation: The Royal Marsden Hospital, London, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nutting
authors.affiliation: Targeted Therapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: McLaughlin
authors.affiliation: Targeted Therapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.|The Royal Marsden Hospital, London, UK.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D059765:Homologous Recombination / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007211:Indoles; D020128:Inhibitory Concentration 50; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects* / Q000528:radiation effects; D009025:Morpholines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013449:Sulfonamides; D013454:Sulfoxides / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; D013454:Sulfoxides; D016159:Tumor Suppressor Protein p53; C000611951:ceralasertib