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Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy

Willoughby, Catherine E., Jiang, Yanyan, Thomas, Huw D., Willmore, Elaine, Kyle, Suzanne, Wittner, Anita, Phillips, Nicole, Zhao, Yan, Tudhope, Susan J., Prendergast, Lisa, Junge, Gesa, Lourenco, Luiza Madia, Finlay, M. Raymond V., Turner, Paul, Munck, Joanne M., Griffin, Roger J., Rennison, Tommy, Pickles, James, Cano, Celine, Newell, Herbie, Reeves, Helen L., Ryan, Anderson J. and Wedge, Stephen R. (2019) Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy. Journal of Clinical Investigation, 130 (1). pp. 258-271. ISSN 0021-9738

Item Type: Article


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 the 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.

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Depositing User: Leah Maughan


Item ID: 12742
Identification Number:
ISSN: 0021-9738
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Date Deposited: 28 Oct 2020 11:13
Last Modified: 28 Oct 2020 11:19


Author: Catherine E. Willoughby
Author: Yanyan Jiang
Author: Huw D. Thomas
Author: Elaine Willmore
Author: Suzanne Kyle
Author: Anita Wittner
Author: Nicole Phillips
Author: Yan Zhao
Author: Susan J. Tudhope
Author: Lisa Prendergast
Author: Gesa Junge
Author: Luiza Madia Lourenco
Author: M. Raymond V. Finlay
Author: Paul Turner
Author: Joanne M. Munck
Author: Roger J. Griffin
Author: Tommy Rennison
Author: James Pickles
Author: Celine Cano
Author: Herbie Newell
Author: Helen L. Reeves
Author: Anderson J. Ryan
Author: Stephen R. Wedge

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Faculty of Health Sciences and Wellbeing > School of Nursing and Health Sciences

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