The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergizes with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.

中文翻译：

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HDAC8 和检查点激酶抑制联合在临床前模型中诱导肿瘤选择性合成致死。


复制应激水平升高是癌细胞的固有特征。靶向维持基因组稳定性的机制以进一步增加复制应激，从而诱导严重的基因组不稳定已成为癌症治疗的一种有前途的方法。在这里，我们将组蛋白脱乙酰酶 8 （HDAC8） 确定为一种药物靶标，其失活与检查点激酶的抑制协同作用，在癌细胞中选择性地引发大量复制应激并损害基因组完整性。我们发现，同时抑制 HDAC8 和检查点激酶导致广泛的复制叉崩溃、不可逆的细胞周期停滞以及各种癌细胞的协同脆弱性。联合治疗的疗效在患者肿瘤来源的类器官 （PDO） 和异种移植小鼠 （PDX） 模型中得到进一步验证，为患者特异性药物反应提供了重要见解。我们的数据显示，HDAC8 活性对于在复制叉之前降低染色体蛋白 3 （SMC3） 结构维持的乙酰化水平和防止 R 环形成至关重要。HDAC8 失活导致分叉进程减慢和检查点激酶激活。我们的研究结果表明，HDAC8 保护复制基因组的完整性，HDAC8 和检查点激酶之间的癌症特异性合成致死性为治疗多种癌症提供了一种有前途的复制应激靶向策略。