The role of PARP inhibitors to radiosensitize liver tumours

Janet HALL, 1Centre de Recherche en Cancérologie de Lyon - UMR Inserm 1052 - CNRS 5286, France
GEROSSIER L. 1 , FARES N. 1 , VACHER S. 2 , BIECHE I. 2 , PEYROT L. 1 , LEFRANCOIS L. 1 , GUILLOT C. 1 , CORTAY J. 1 , CARON DE FROMENTAL C. 1 , MERLE P. 1 , HANZ O. 1 , CHEMIN I. 1

1 Immunity, Virus and Inflammation Team, Centre de Recherche en Cancérologie de Lyon - UMR Inserm 1052 - CNRS 5286, Lyon, France
2 2Institut Curie – Hôpital, Unité de Pharmacogénomique, Service de Génétique, Département de Biologie des Tumeurs, Paris Cedex 05, France

As over 50% of all cancer patients will receive radiotherapy there is considerable interest in the development of radiosensitisers that could replace chemotherapeutic agents without the associated dose-limiting toxicities.  Small molecules inhibitors of poly(ADP-ribose) polymerases (PARPs), key proteins in the DNA damage response (DDR), are one example of this drug class that are entering into clinical trials. Based on this strong rational and the fact that radiotherapy has been shown to be a promising approach for hepatocellular carcinoma (HCC) treatment we are assessing this combined treatment strategy in HCC cell lines. In a first series of experiments 4/7 HCC lines were sensitive to the PARP inhibitor ABT-888 given as a single 2 hour exposure, with the two cell lines tested showing enhanced radiosensitivity when irradiated in its presence (Guillot et al., BMC Cancer, 14 (2014) 603). As Hepatitis B virus (HBV) infection is a major cause of HCC and HBV proteins modify the DNA damage response, these studies have now been extended to examine radiation sensitivity in cell models expressing or not HBV viral proteins.  Greater radiation sensitivity was seen in two HBV expressing lines compared to the parental line and these lines also showed a greater gain in sensitivity when irradiated in the presence of ABT-888. In parallel studies the variation in expression of PARP proteins in liver cancers of different etiology is being examined. Paradoxically in the light of the in vitro results PARP-1 mRNA levels were found to be highest in the panel of HBV-HCC compared to HCV or alcohol associated HCCs and increased relative to the peritumour tissue. Studies are underway to identify which viral proteins contribute to this cellular phenotype and to dissect the impact on the DDR.
 
Financial support of La Ligue Nationale du Cancer Comité du Rhône is gratefully acknowledged.