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Ref Type Journal Article
PMID (28062704)
Authors Dillon MT, Barker HE, Pedersen M, Hafsi H, Bhide SA, Newbold KL, Nutting CM, McLaughlin M, Harrington KJ
Title Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 16 1 2017 Jan 25-34 Mol Cancer Ther
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 wild-type lung carcinoma sensitive Ceralasertib + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, AZD6738 treatment increased sensitivity to radiotherapy in a lung carcinoma cell line harboring wild-type TP53 in culture, resulting in a greater decrease in cell survival compared to radiation treatment alone (PMID: 28062704). 28062704
TP53 mutant tongue squamous cell carcinoma sensitive Ceralasertib + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, AZD6738 treatment increased sensitivity to radiotherapy in a tongue squamous cell carcinoma cell line harboring a TP53 mutation in culture, resulting in a greater decrease in cell survival compared to radiation treatment alone (PMID: 28062704). 28062704
TP53 mutant pharynx squamous cell carcinoma sensitive Ceralasertib + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, AZD6738 treatment increased sensitivity to radiotherapy in a pharynx squamous cell carcinoma cell line harboring a TP53 mutation in culture, resulting in a greater decrease in cell survival compared to radiation treatment alone (PMID: 28062704). 28062704
TP53 loss colorectal cancer sensitive Ceralasertib + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, AZD6738 increased sensitivity to radiotherapy in colorectal cancer xenograft models harboring a loss of TP53, resulting in a greater delay of tumor growth compared to radiation alone and an improved survival compared to control or either agent alone (PMID: 28062704). 28062704