Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy
Catherine E. Willoughby, … , Anderson J. Ryan, Stephen R. Wedge
Catherine E. Willoughby, … , Anderson J. Ryan, Stephen R. Wedge
Published October 3, 2019
Citation Information: J Clin Invest. 2020;130(1):258-271. https://doi.org/10.1172/JCI127483.
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Research Article Oncology

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

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 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.

Authors

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

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Figure 3

NU5455 preferentially augments radiotherapy in subcutaneous Calu-6 and A549 lung tumor xenografts versus surrounding skin.

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NU5455 preferentially augments radiotherapy in subcutaneous Calu-6 and A...
(A) Mean tumor volume of mice bearing Calu-6 subcutaneous xenografts treated with NU5455 (30 mg/kg orally) or vehicle 30 minutes before localized radiation (0 Gy or 3.3 Gy, 4–5 mice per group). (B and C) Number of γH2AX foci per nucleus in subcutaneous Calu-6 tumors (B) and the surrounding skin (C) collected 5 and 24 hours after irradiation (3 mice per group). (D) NU5455 concentrations in the plasma, lung, skin, and subcutaneous Calu-6 tumors 15–360 minutes after oral administration of NU5455 (30 mg/kg, 3 mice per group). (E) Volume of subcutaneous Calu-6 tumors following treatment with NU5455 (30 mg/kg orally) or vehicle 30 minutes after localized radiation (0 Gy or 10 Gy, 4–6 mice per group). (F) Corresponding percentage change in body weight of mice bearing Calu-6 tumors. (G) Number of 53BP1 and γH2AX foci per nucleus in Calu-6 tumors collected 24 hours after irradiation (3 mice per group). (H) Mean tumor volume from mice bearing A549 subcutaneous xenografts treated with NU5455 (30 mg/kg orally) or vehicle 30 minutes before localized radiation (0 Gy or 10 Gy, 4–5 mice per group). (I) Number of 53BP1 and γH2AX foci per nucleus in A549 tumors collected 24 hours after irradiation (3 mice per group). All graphs represent the mean ± SEM. Statistical significance was assessed using unpaired t tests, with the exception of G and I, for which it was assessed by 1-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.