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 6

NU5455 sensitizes tumors to topoisomerase II inhibitors but has a narrow therapeutic index when combined with systemic chemotherapy in vivo.

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NU5455 sensitizes tumors to topoisomerase II inhibitors but has a narrow...
(A) Clonogenic survival of Huh7 and SJSA-1 cells pretreated with vehicle or NU5455 (1 μM) for 1 hour before the addition of doxorubicin or etoposide for 24 hours before replating into drug-free media. (B) LD80 values from clonogenic survival assays of human tumor cell lines pretreated with vehicle or NU5455 (1 μM) for 1 hour before the addition of doxorubicin or etoposide for 24 hours before reseeding into drug-free media. Fold potentiation is indicated for each cell line. A and B depict the mean ± SEM from 3 independent experiments. (C) Mice bearing subcutaneous SJSA-1 tumor xenografts (103–121 mm3) were treated with NU5455 (100 mg/kg orally) with or without etoposide (5 mg/kg, i.p.) daily for 5 days. (D) Mean SJSA-1 tumor volume, and percentage body weight at day 8 relative to pretreatment body weight on day 1 (5–10 mice per group). †Humane intervention was required at day 8 for 2 of 10 mice receiving combination treatment. All graphs represent the mean ± SEM. Statistical significance was assessed using unpaired t tests (A and B) and 1-way ANOVA (D). *P < 0.05, **P < 0.01, ***P < 0.001.