PARP inhibitors and radiation potentiate liver cell death in vitro. Do hepatocellular carcinomas have an achilles’ heel?

摘要: Abstract Background A promising avenue for cancer treatment is exacerbating the deregulation of DNA repair machinery that would normally protect genome. To address applicability poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) combined with radiotherapy hepatocellular carcinoma (HCC) two approaches were used: firstly, in vitro sensitivity to PARPi Veliparib and Talazoparib +/- radiation exposure was determined liver cell lines impact HBV X protein (HBx) deregulates cellular damage via SMC5/6 degradation investigated. Secondly, PARP expression profiles levels using surrogate marker gammaH2AX assessed a panel control vs HCC tissues. Methods Cell cytotoxicity measured by clonogenic survival or relative growth response immunological-based techniques Hep3B, PLC/PRF/5, HepG2- HepaRG-derived models. Transcriptome changes due HBx SMC6 loss RNA sequencing PARG transcripts (qPCR) PARP1, H2AX (RPPA) compared HBV-, HCV-, alcohol- non-alcoholic steatohepatitis-associated (tumor/peritumor) Results significantly enhanced when X-rays (2 Gy) having greater than most lowered survival, probably driven based on transcriptome analysis higher levels. PARP1 PARP2 transcript tumor peritumor The HBV/HCV/alcohol-associated tissues studied had reduced but providing evidence increased during disease progression. Conclusions These proof-of-concept experiments support alone treatment, particularly HBV-associated tumors, warrant further investigation.