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Selective DNA-PKcs Inhibition Extends the Therapeutic Index of Localized Radiotherapy and Chemotherapy

Lookup NU author(s): Dr Catherine Willoughby, Huw Thomas, Dr Elaine Willmore, Suzanne Kyle, Dr Anita Wittner, Nicole Phillips, Dr Yan Zhao, Dr Susan Tudhope, Dr Lisa Prendergast, Gesa Junge, Professor Roger Griffin, Dr Tommy Rennison, James Pickles, Dr Celine Cano, Emeritus Professor Herbie Newell, Professor Helen Reeves, Professor Steve Wedge

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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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