Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei.
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Date
2017-01-01Author
Dillon, MT
Barker, HE
Pedersen, M
Hafsi, H
Bhide, SA
Newbold, KL
Nutting, CM
McLaughlin, M
Harrington, KJ
Type
Journal Article
Metadata
Show full item recordAbstract
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 G2 cell-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.
Collections
Subject
Cell Line, Tumor
Micronuclei, Chromosome-Defective
Animals
Humans
Mice
DNA Damage
Disease Models, Animal
Sulfoxides
Pyrimidines
Protein Kinase Inhibitors
Radiation-Sensitizing Agents
Tumor Burden
Xenograft Model Antitumor Assays
Inhibitory Concentration 50
Radiation, Ionizing
Radiation Tolerance
Tumor Suppressor Protein p53
Homologous Recombination
G2 Phase Cell Cycle Checkpoints
Research team
Targeted Therapy
Language
eng
Date accepted
2016-11-01
License start date
2017-01
Citation
Molecular cancer therapeutics, 2017, 16 (1), pp. 25 - 34
Publisher
AMER ASSOC CANCER RESEARCH