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

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.

SUBMITTER: Wang C

PROVIDER: S-EPMC7584895 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Wang Chen C Tang Huanyin H Geng Anke A Dai Binghua B Zhang Haiping H Sun Xiaoxiang X Chen Yu Y Qiao Zhibing Z Zhu Hong H Yang Jiamei J Chen Jiayu J He Qizhi Q Qin Nan N Xie Jinru J Tan Rong R Wan Xiaoping X Gao Shaorong S Jiang Ying Y Sun Fang-Lin FL Mao Zhiyong Z

Proceedings of the National Academy of Sciences of the United States of America 20201005 42

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 f ...[more]

PMID: 33020270

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Project description:BackgroundHepatocellular carcinoma (HCC) remains difficult to treat due to limited effective treatment options. While the proteasome inhibitor bortezomib has shown promising preclinical activity in HCC, clinical trials of bortezomib showed no advantage over the standard-of-care treatment sorafenib, highlighting the need for more clinically relevant therapeutic strategies. Here, we propose that rational drug combination design and validation in patient-derived HCC avatar models such as patient-derived xenografts (PDXs) and organoids can improve proteasome inhibitor-based therapeutic efficacy and clinical potential.MethodsHCC PDXs and the corresponding PDX-derived organoids (PDXOs) were generated from primary patient samples for drug screening and efficacy studies. To identify effective proteasome inhibitor-based drug combinations, we applied a hybrid experimental-computational approach, Quadratic Phenotypic Optimization Platform (QPOP) on a pool of nine drugs comprising proteasome inhibitors, kinase inhibitors and chemotherapy agents. QPOP utilizes small experimental drug response datasets to accurately identify globally optimal drug combinations.ResultsPreliminary drug screening highlighted the increased susceptibility of HCC PDXOs towards proteasome inhibitors. Through QPOP, the combination of second-generation proteasome inhibitor ixazomib (Ixa) and CDK inhibitor dinaciclib (Dina) was identified to be effective against HCC. In vitro and in vivo studies demonstrated the synergistic pro-apoptotic and anti-proliferative activity of Ixa + Dina against HCC PDXs and PDXOs. Furthermore, Ixa + Dina outperformed sorafenib in mitigating tumor formation in mice. Mechanistically, increased activation of JNK signaling mediates the combined anti-tumor effects of Ixa + Dina in HCC tumor cells.ConclusionsRational drug combination design in patient-derived avatars highlights the therapeutic potential of proteasome and CDK inhibitors and represents a feasible approach towards developing more clinically relevant treatment strategies for HCC.

Dataset Information

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

Publications

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

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