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

Authors:
Publisher website
Google Scholar
Abstract
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. Significance Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, and its mortality rate continues to increase. We generated knock-in reporter mouse models for measuring DNA double-strand break (DSB) repair efficiency and demonstrated that both DSB repair pathways are up-regulated in mouse HCCs. We then found that activation of PARP1 and DNA-PKcs is critical to HCC survival bothin vitro and in vivo. Targeting the two proteins to block both DSB repair pathways by combining olaparib and NU7441 synergistically inhibits HCC growth in both orthotopic HCC mouse and human PDX models. Our work not only establishes versatile tools for in vivo analysis of DNA repair, but also implies an effective combination therapy for HCC.

This publication has 43 references indexed in Scilit: