Open AccessRational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors
Author(s) -
Chen Wang,
Herman Tang,
Anke Geng,
Binghua Dai,
Haiping Zhang,
Xian-He Sun,
Yu Chen,
Zhibing Qiao,
Hong Zhu,
Jiamei Yang,
Jiayu Chen,
Qizhi He,
Nan Qin,
Jinru Xie,
Rong Tan,
Xiaoping Wan,
Shaorong Gao,
Ying Jiang,
Fang-Lin Sun,
Zhiyong Mao
Publication year - 2020
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2002917117
Subject(s) - olaparib , parp1 , in vivo , cancer research , hepatocellular carcinoma , hccs , dna repair , dna damage , dna , biology , chemistry , medicine , poly adp ribose polymerase , polymerase , genetics
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 knock-in 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.