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Lookup NU author(s): Dr Catherine WilloughbyORCiD, Huw ThomasORCiD, Dr Elaine WillmoreORCiD, Suzanne Kyle, Dr Anita Wittner, Nicole Phillips, Dr Yan Zhao, Dr Susan Tudhope, Dr Lisa PrendergastORCiD, Gesa Junge, Professor Roger Griffin, Dr Tommy Rennison, James Pickles, Dr Celine CanoORCiD, Professor Herbie Newell, Professor Helen ReevesORCiD, Professor Steve Wedge
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly-identified highly-selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted-radiotherapy on human orthotopic lung tumors without influencing acute DNA-damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and toxicity of a parenterally-administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.
Author(s): Willoughby CE, Jiang Y, Thomas HD, Willmore E, Kyle S, Wittner A, Phillips N, Zhao Y, Tudhope SJ, Prendergast L, Junge G, Lourenco LM, Finlay MRV, Turner P, Munck JM, Griffin RJ, Rennison T, Pickles J, Cano C, Newell DR, Reeves HL, Ryan AJ, Wedge SR
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Investigation
Year: 2019
Volume: 130
Pages: 1-14
Print publication date: 25/11/2019
Online publication date: 03/10/2019
Acceptance date: 25/09/2019
Date deposited: 11/12/2019
ISSN (print): 0021-9738
ISSN (electronic): 1558-8238
Publisher: American Society for Clinical Investigation
URL: https://doi.org/10.1172/JCI127483
DOI: 10.1172/JCI127483
PubMed id: 31581151
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