Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:130 |
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| Enthalten in: |
The Journal of clinical investigation - 130(2020), 1 vom: 02. Jan., Seite 258-271 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Willoughby, Catherine E [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.07.2020 Date Revised 10.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1172/JCI127483 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM301884196 |
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| 100 | 1 | |a Willoughby, Catherine E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy |
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| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DNA repair | |
| 650 | 4 | |a Liver cancer | |
| 650 | 4 | |a Oncology | |
| 650 | 4 | |a Radiation therapy | |
| 650 | 4 | |a Therapeutics | |
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| 700 | 1 | |a Jiang, Yanyan |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Huw D |e verfasserin |4 aut | |
| 700 | 1 | |a Willmore, Elaine |e verfasserin |4 aut | |
| 700 | 1 | |a Kyle, Suzanne |e verfasserin |4 aut | |
| 700 | 1 | |a Wittner, Anita |e verfasserin |4 aut | |
| 700 | 1 | |a Phillips, Nicole |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Tudhope, Susan J |e verfasserin |4 aut | |
| 700 | 1 | |a Prendergast, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Junge, Gesa |e verfasserin |4 aut | |
| 700 | 1 | |a Lourenco, Luiza Madia |e verfasserin |4 aut | |
| 700 | 1 | |a Finlay, M Raymond V |e verfasserin |4 aut | |
| 700 | 1 | |a Turner, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Munck, Joanne M |e verfasserin |4 aut | |
| 700 | 1 | |a Griffin, Roger J |e verfasserin |4 aut | |
| 700 | 1 | |a Rennison, Tommy |e verfasserin |4 aut | |
| 700 | 1 | |a Pickles, James |e verfasserin |4 aut | |
| 700 | 1 | |a Cano, Celine |e verfasserin |4 aut | |
| 700 | 1 | |a Newell, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Reeves, Helen L |e verfasserin |4 aut | |
| 700 | 1 | |a Ryan, Anderson J |e verfasserin |4 aut | |
| 700 | 1 | |a Wedge, Stephen R |e verfasserin |4 aut | |
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