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DNA-PK-A Candidate Driver of Hepatocarcinogenesis and Tissue Biomarker That Predicts Response to Treatment and Survival

Lookup NU author(s): Liam Cornell, Dr Joanne Munck, Laura Ogle, Dr Catherine Willoughby, Dr Despina Televantou, Huw Thomas, Dr Jennifer Jackson, Professor Alastair Burt, Professor Herbie Newell, Dr John Rose, Professor Derek Manas, Professor Nicola Curtin, Professor Helen Reeves

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Abstract

Purpose: 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.Experimental Design: 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. (C)2014 AACR.


Publication metadata

Author(s): Cornell L, Munck JM, Alsinet C, Villanueva A, Ogle L, Willoughby CE, Televantou D, Thomas HD, Jackson J, Burt AD, Newell D, Rose J, Manas DM, Shapiro GI, Curtin NJ, Reeves HL

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2015

Volume: 21

Issue: 4

Pages: 925-933

Print publication date: 15/02/2015

Online publication date: 05/12/2014

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1078-0432.CCR-14-0842

DOI: 10.1158/1078-0432.CCR-14-0842


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