title: DNA-PK-A candidate driver of hepatocarcinogenesis and tissue biomarker that predicts response to treatment and survival.
abstract: OBJECTIVE
  Therapy resistance and associated liver disease make hepatocellular carcinomas (HCC) difficult to treat with traditional cytotoxic therapies, whereas newer targeted approaches offer only modest survival benefit. We focused on DNA-dependent protein kinase, DNA-PKcs, encoded by PRKDC and central to DNA damage repair by nonhomologous end joining. Our aim was to explore its roles in hepatocarcinogenesis and as a novel therapeutic candidate.
  
  
  METHODS
  PRKDC was characterized in liver tissues from of 132 patients [normal liver (n = 10), cirrhotic liver (n = 13), dysplastic nodules (n = 18), HCC (n = 91)] using Affymetrix U133 Plus 2.0 and 500 K Human Mapping SNP arrays (cohort 1). In addition, we studied a case series of 45 patients with HCC undergoing diagnostic biopsy (cohort 2). Histological grading, response to treatment, and survival were correlated with DNA-PKcs quantified immunohistochemically. Parallel in vitro studies determined the impact of DNA-PK on DNA repair and response to cytotoxic therapy.
  
  
  RESULTS
  Increased PRKDC expression in HCC was associated with amplification of its genetic locus in cohort 1. In cohort 2, elevated DNA-PKcs identified patients with treatment-resistant HCC, progressing at a median of 4.5 months compared with 16.9 months, whereas elevation of activated pDNA-PK independently predicted poorer survival. DNA-PKcs was high in HCC cell lines, where its inhibition with NU7441 potentiated irradiation and doxorubicin-induced cytotoxicity, whereas the combination suppressed HCC growth in vitro and in vivo.
  
  
  CONCLUSIONS
  These data identify PRKDC/DNA-PKcs as a candidate driver of hepatocarcinogenesis, whose biopsy characterization at diagnosis may impact stratification of current therapies, and whose specific future targeting may overcome resistance.
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom. Early Drug Development Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Liam
authors.initials: L
authors.lastname: Cornell
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Munck
authors.affiliation: Barcelona Clinic Liver Cancer Group (BCLC, Translational Research laboratory and Liver Unit), Hospital Clinic, IDIBAPS, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Alsinet
authors.affiliation: Barcelona Clinic Liver Cancer Group (BCLC, Translational Research laboratory and Liver Unit), Hospital Clinic, IDIBAPS, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain. Institute of Liver Studies, Division of Transplantation and Mucosal Biology, King's College, Denmark Hill, London, United Kingdom.
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Ogle
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Willoughby
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Despina
authors.initials: D
authors.lastname: Televantou
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jackson
authors.affiliation: Institute of Cell and Molecular Biosciences, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom. School of Medicine, The University of Adelaide, Adelaide, Australia.
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Burt
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Newell
authors.affiliation: Radiology Department, The Freeman Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Rose
authors.affiliation: Hepatopancreatobiliary Team, The Freeman Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Manas
authors.affiliation: Early Drug Development Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom. Nicola.curtin@ncl.ac.uk.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.affiliation: Northern Institute for Cancer Research, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom. Hepatopancreatobiliary Team, The Freeman Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Reeves
mesh_terms: D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051747:DNA-Activated Protein Kinase / Q000096:biosynthesis*; D005260:Female; D005784:Gene Amplification; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human