Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy

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Abstract

Background and purpose: To evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced fibrosis. Materials and methods: AZD6738 was evaluated as a monotherapy and in combination with radiation in vitro and in vivo using A549 and H460 NSCLC models. Radiation induced pulmonary fibrosis was evaluated by cone beam computed tomography (CBCT) and histological staining. Results: AZD6738 specifically inhibits ATR kinase and enhanced radiobiological response in NSCLC models but not in human bronchial epithelial cells (HBECs) in vitro. Significant tumour growth delay was observed in cell line derived xenografts (CDXs) of H460 cells (p < 0.05) which were less significant in A549 cells. Combination of AZD6738 with radiotherapy showed no significant change in lung tissue density by CBCT (p > 0.5) and histological scoring of radiation induced fibrosis (p > 0.5). Conclusion: Inhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC.
Original languageEnglish
Pages (from-to)475-481
JournalRadiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
Volume124
Issue number3
Early online date08 Jul 2017
DOIs
Publication statusEarly online date - 08 Jul 2017

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Ataxia Telangiectasia
Non-Small Cell Lung Carcinoma
Radiotherapy
Radiation Pneumonitis
Radiation
Neoplasms
Cone-Beam Computed Tomography
Pulmonary Fibrosis
Therapeutics
Growth
Heterografts
Phosphotransferases
Epithelial Cells
Staining and Labeling
Cell Line
In Vitro Techniques

Keywords

  • Journal Article

Cite this

@article{e89fd204533043e78fec5a679614ddee,
title = "Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy",
abstract = "Background and purpose: To evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced fibrosis. Materials and methods: AZD6738 was evaluated as a monotherapy and in combination with radiation in vitro and in vivo using A549 and H460 NSCLC models. Radiation induced pulmonary fibrosis was evaluated by cone beam computed tomography (CBCT) and histological staining. Results: AZD6738 specifically inhibits ATR kinase and enhanced radiobiological response in NSCLC models but not in human bronchial epithelial cells (HBECs) in vitro. Significant tumour growth delay was observed in cell line derived xenografts (CDXs) of H460 cells (p < 0.05) which were less significant in A549 cells. Combination of AZD6738 with radiotherapy showed no significant change in lung tissue density by CBCT (p > 0.5) and histological scoring of radiation induced fibrosis (p > 0.5). Conclusion: Inhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC.",
keywords = "Journal Article",
author = "Victoria Dunne and Mihaela Ghita and Small, {Donna M} and Coffey, {Caroline B M} and Sinead Weldon and Taggart, {Clifford C} and Osman, {Sarah O} and McGarry, {Conor K} and Prise, {Kevin M} and Hanna, {Gerard G} and Butterworth, {Karl T}",
note = "Crown Copyright {\circledC} 2017. Published by Elsevier B.V. All rights reserved.",
year = "2017",
month = "7",
day = "8",
doi = "10.1016/j.radonc.2017.06.025",
language = "English",
volume = "124",
pages = "475--481",
journal = "Radiotherapy and Oncology",
issn = "0167-8140",
publisher = "Elsevier",
number = "3",

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TY - JOUR

T1 - Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy

AU - Dunne, Victoria

AU - Ghita, Mihaela

AU - Small, Donna M

AU - Coffey, Caroline B M

AU - Weldon, Sinead

AU - Taggart, Clifford C

AU - Osman, Sarah O

AU - McGarry, Conor K

AU - Prise, Kevin M

AU - Hanna, Gerard G

AU - Butterworth, Karl T

N1 - Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

PY - 2017/7/8

Y1 - 2017/7/8

N2 - Background and purpose: To evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced fibrosis. Materials and methods: AZD6738 was evaluated as a monotherapy and in combination with radiation in vitro and in vivo using A549 and H460 NSCLC models. Radiation induced pulmonary fibrosis was evaluated by cone beam computed tomography (CBCT) and histological staining. Results: AZD6738 specifically inhibits ATR kinase and enhanced radiobiological response in NSCLC models but not in human bronchial epithelial cells (HBECs) in vitro. Significant tumour growth delay was observed in cell line derived xenografts (CDXs) of H460 cells (p < 0.05) which were less significant in A549 cells. Combination of AZD6738 with radiotherapy showed no significant change in lung tissue density by CBCT (p > 0.5) and histological scoring of radiation induced fibrosis (p > 0.5). Conclusion: Inhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC.

AB - Background and purpose: To evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced fibrosis. Materials and methods: AZD6738 was evaluated as a monotherapy and in combination with radiation in vitro and in vivo using A549 and H460 NSCLC models. Radiation induced pulmonary fibrosis was evaluated by cone beam computed tomography (CBCT) and histological staining. Results: AZD6738 specifically inhibits ATR kinase and enhanced radiobiological response in NSCLC models but not in human bronchial epithelial cells (HBECs) in vitro. Significant tumour growth delay was observed in cell line derived xenografts (CDXs) of H460 cells (p < 0.05) which were less significant in A549 cells. Combination of AZD6738 with radiotherapy showed no significant change in lung tissue density by CBCT (p > 0.5) and histological scoring of radiation induced fibrosis (p > 0.5). Conclusion: Inhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC.

KW - Journal Article

U2 - 10.1016/j.radonc.2017.06.025

DO - 10.1016/j.radonc.2017.06.025

M3 - Article

C2 - 28697853

VL - 124

SP - 475

EP - 481

JO - Radiotherapy and Oncology

JF - Radiotherapy and Oncology

SN - 0167-8140

IS - 3

ER -