Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer

Yuchen Guo,Xiaohang Qiao,Cun Wang,Bente Benedict,Chong Sun,Jun Wang,Hein Te Riele,Shu Zhang,René Bernards,Wenxin Qin,Dongmei Gao,Frank Van Gemert,Roderick L Beijersbergen,Qiang Gao,Xuhui Ma,Hui Wang,Chen Yang,Cor Lieftink

doi:10.1186/s13073-021-00981-0

Abstract

BackgroundLiver cancer is one of the most commonly diagnosed cancers and the fourth leading cause of cancer-related death worldwide. Broad-spectrum kinase inhibitors like sorafenib and lenvatinib provide only modest survival benefit to patients with hepatocellular carcinoma (HCC). This study aims to identify novel therapeutic strategies for HCC patients.MethodsIntegrated bioinformatics analyses and a non-biased CRISPR loss of function genetic screen were performed to identify potential therapeutic targets for HCC cells. Whole-transcriptome sequencing (RNA-Seq) and time-lapse live imaging were performed to explore the mechanisms of the synergy between CDC7 inhibition and ATR or CHK1 inhibitors in HCC cells. Multiple in vitro and in vivo assays were used to validate the synergistic effects.ResultsThrough integrated bioinformatics analyses using the Cancer Dependency Map and the TCGA database, we identified ATR-CHK1 signaling as a therapeutic target for liver cancer. Pharmacological inhibition of ATR or CHK1 leads to robust proliferation inhibition in liver cancer cells having a high basal level of replication stress. For liver cancer cells that are resistant to ATR or CHK1 inhibition, treatment with CDC7 inhibitors induces strong DNA replication stress and consequently such drugs show striking synergy with ATR or CHK1 inhibitors. The synergy between ATR-CHK1 inhibition and CDC7 inhibition probably derives from abnormalities in mitosis inducing mitotic catastrophe.ConclusionsOur data highlights the potential of targeting ATR-CHK1 signaling, either alone or in combination with CDC7 inhibition, for the treatment of liver cancer.

Highlights

Liver cancer is one of the most commonly diagnosed cancers and the fourth leading cause of cancerrelated death worldwide
ATR and CHK1 are potential therapeutic targets for liver cancer To evaluate the activity of the DNA damage response (DDR) in hepatocellular carcinoma (HCC) tissues, we first performed gene set enrichment analyses on RNAsequencing data of 50 paired tumor and non-tumor tissues from the TCGA database
To explore genes involved in the DDR as potential drug targets in HCC therapy, we analyzed the gene dependencies of liver cancer cell lines (n = 22) in the dependency map (DepMap) public dataset

Summary

Introduction

Liver cancer is one of the most commonly diagnosed cancers and the fourth leading cause of cancerrelated death worldwide. Broad-spectrum kinase inhibitors like sorafenib and lenvatinib provide only modest survival benefit to patients with hepatocellular carcinoma (HCC). A multi-kinase inhibitor approved by US Food and Drug Administration (FDA) as the standard therapy for advanced HCC patients in 2007, only provides less than 3-months benefit in median overall survival [2]. The recent IMbrave150 trial indicates that the combination of atezolizumab and bevacizumab resulted in better survival outcomes than sorafenib monotherapy, providing a confirmed objective response rate of 27.3% [11]. Despite this progress, further investigations of novel therapeutic strategies are urgently required to counter this lethal disease

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