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Published on: May 24, 2024
Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors
Chen Wang1,2,3, Huanyin Tang1, Anke Geng1
1Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
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.
Insights
Targeting DNA repair in hepatocellular carcinoma (HCC) is promising. Inhibiting homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways synergistically suppressed HCC growth, suggesting a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DNA double-strand breaks (DSBs) are critical DNA lesions.
- Understanding DSB repair pathway differences between tumor and normal tissues is key for targeted cancer therapy.
- Hepatocellular carcinoma (HCC) exhibits altered DNA repair mechanisms.
Purpose of the Study:
- To investigate the efficiency of homologous recombination (HR) and nonhomologous end-joining (NHEJ) in HCC.
- To explore the therapeutic potential of inhibiting DSB repair pathways in HCC.
Main Methods:
- Utilized knock-in mouse models to measure HR and NHEJ efficiency.
- Administered PARP1 inhibitor (olaparib) and DNA-PKcs inhibitor (NU7441).
- Assessed tumor growth in mouse and patient-derived xenograft models.
Main Results:
- Both HR and NHEJ pathways are upregulated in HCC compared to normal tissues.
- PARP1 inhibition abrogated HR repair in HCC by affecting nucleosome clearance and RPA2/RAD51 recruitment.
- Combined inhibition of PARP1 and DNA-PKcs synergistically suppressed HCC growth.
Conclusions:
- Combined inhibition of HR and NHEJ represents a potential therapeutic strategy for HCC.
- Altered expression of DNA repair factors like PARP1 and DNA-PKcs contributes to HCC progression.
- Targeting DNA repair pathways offers a novel approach for HCC treatment.
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