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.
View: Text | PDF
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

×

Figure 5

NU5455 augments the effect of fractionated radiotherapy in Calu-6 tumors without enhancing late radiation damage to the lung.

Options: View larger image (or click on image) Download as PowerPoint
NU5455 augments the effect of fractionated radiotherapy in Calu-6 tumors...
(A) Mean tumor volume of mice bearing Calu-6 subcutaneous xenografts treated with localized radiation (4 × 5 Gy on days 1, 4, 7, and 10) with either NU5455 (30 mg/kg orally) or vehicle 30 minutes before and 5 hours after each dose of IR (3–5 mice per group). The time taken to reach 2 times the tumor volume at the start of treatment (RTV2) was also assessed. (B) Masson’s trichrome staining was used to evaluate lung fibrosis in mice 24 weeks after treatment with thoracic radiation (4 × 5 Gy on days 1, 4, 7, and 10) with or without NU5455 (30 mg/kg orally) or vehicle 30 minutes before and 5 hours after each dose of IR. Samples were scored using the modified Ashcroft system on a scale of 0 to 8 (5–9 mice per group). Representative images are depicted. Scale bars: 100 μm (main images) and 4 mm (inset images). All graphs represent the mean ± SEM. Statistical significance was assessed using a log-rank test (A) and 1-way ANOVA (B). *P < 0.05, **P < 0.01, ****P < 0.0001.