Journal Article

Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors

Zhang, Haiping, Zhu, Hong, Geng, Anke, Chen, Yu, Qin, Nan, Tang, Huanyin, Dai, Binghua, Xie, Jinru, Jiang, Ying, He, Qizhi, Tan, Rong, Qiao, Zhibing, Sun, Xiaoxiang, Sun, Fang-Lin, Wang, Chen, Mao, Zhiyong, Yang, Jiamei, Wan, Xiaoping, Gao, Shaorong, Chen, Jiayu

2020

Overview

Understanding differences in DNA double-strand break (DSB) repair between tumor and normal tissues would provide a rationale for developing DNA repair-targeted cancer therapy. Here, using knockin mouse models for measuring the efficiency of two DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ), we demonstrated that both pathways are up-regulated in hepatocellular carcinoma (HCC) compared with adjacent normal tissues due to altered expression of DNA repair factors, including PARP1 and DNA-PKcs. Surprisingly, inhibiting PARP1 with olaparib abrogated HR repair in HCC. Mechanistically, inhibiting PARP1 suppressed the clearance of nucleosomes at DNA damage sites by blocking the recruitment of ALC1 to DSB sites, thereby inhibiting RPA2 and RAD51 recruitment. Importantly, combining olaparib with NU7441, a DNA-PKcs inhibitor that blocks NHEJ in HCC, synergistically suppressed HCC growth in both mice and HCC patient-derived-xenograft models. Our results suggest the combined inhibition of both HR and NHEJ as a potential therapy for HCC.

• Publisher: National Academy of Sciences
• Subject: Animal models / Animals / Biological Sciences / Cancer / Carcinoma, Hepatocellular - drug therapy / Chromones - pharmacology / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded - drug effects / DNA Damage / DNA End-Joining Repair - drug effects / DNA repair / DNA Repair - drug effects / DNA-Binding Proteins - metabolism / DNA-dependent protein kinase / Double-strand break repair / Drug Therapy, Combination - methods / Gene expression / Gene Knock-In Techniques / Hepatocellular carcinoma / Homologous Recombination / Homology / Humans / Liver cancer / Liver Neoplasms - drug therapy / Medical Sciences / Mice / Mice, Nude / Morpholines - pharmacology / Non-homologous end joining / Nucleosomes / Phthalazines - pharmacology / Piperazines - pharmacology / Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors / Poly (ADP-Ribose) Polymerase-1 - metabolism / Poly(ADP-ribose) polymerase / Protein kinase C / Recombinational DNA Repair - drug effects / Recruitment / Repair / Therapy / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation / Yeast