2. Academic Validation
  3. Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy

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

  • J Clin Invest. 2020 Jan 2;130(1):258-271. doi: 10.1172/JCI127483.
Catherine E Willoughby 1,  Yanyan Jiang 2,  Huw D Thomas 1,  Elaine Willmore 1,  Suzanne Kyle 1,  Anita Wittner 1,  Nicole Phillips 1,  Yan Zhao 1,  Susan J Tudhope 1,  Lisa Prendergast 1,  Gesa Junge 1,  Luiza Madia Lourenco 2,  M Raymond V Finlay 3,  Paul Turner 3,  Joanne M Munck 4,  Roger J Griffin 5,  Tommy Rennison 5,  James Pickles 5,  Celine Cano 5,  David R Newell 1,  Helen L Reeves 1 6,  Anderson J Ryan 2,  Stephen R Wedge 1
Affiliations

Affiliations

  • 1 Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • 2 Cancer Research UK and UK Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.
  • 3 Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
  • 4 Astex Pharmaceuticals, Cambridge, United Kingdom.
  • 5 Cancer Research UK Newcastle Drug Discovery Unit, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • 6 Hepatopancreatobiliary Multidisciplinary Team, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
PMID: 31581151 DOI: 10.1172/JCI127483
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.

Keywords

DNA repair; Liver cancer; Oncology; Radiation therapy; Therapeutics.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145427
    DNA-PK抑制剂
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