Reference Detail

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 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 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 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