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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 Therapeutics

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

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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 1

NU5455 is a selective inhibitor of DNA-PKcs activity.

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NU5455 is a selective inhibitor of DNA-PKcs activity.
(A) Chemical struc...
(A) Chemical structure of the DNA-PK inhibitor NU5455 (molecular weight = 595.71). The in vitro potency of NU5455 against DNA-PK and other kinases was assessed by SelectScreen Profiling (Life Technologies). Data depicted graphically represent the cell-free NU5455 IC50 values for PI3K family members (mean ± SEM, n = 4–7) and inhibitory activity of 1 μM NU5455 when tested against a panel of 345 wild-type kinases. (B and C) Changes in phospho–DNA-PK Ser2056 and phospho–AKT Ser473 30 minutes after treatment with 10 Gy IR or 50 ng/mL IGF-1, respectively, in MCF7 cells pretreated with vehicle, NU5455, or NU7441 for 1 hour. Percentage activity was determined relative to total DNA-PK or AKT using densitometry. (D) Plasmid repair assay enabling quantification of NHEJ-mediated DSB repair in HEK293T cells by measurement of the relative proportions of BFP and GFP. Cells were transfected with intact or linearized (AfeI or ScaI restriction endonuclease–treated) plasmid DNA and treated with NU5455 for 24 hours. With the exception of the broad kinase panel screen, all data represent the mean ± SEM from 4–7 (A) and 3 (B–D) independent experiments. Statistical significance was assessed using unpaired t tests (B and C) and 2-way ANOVA (D). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
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