Inducing and exploiting vulnerabilities for the treatment of liver cancer
Inducing and exploiting vulnerabilities for the treatment of liver cancer
复制标题
诱导和利用肝癌治疗的弱点
DOI：
10.1038/s41586-019-1607-3
复制
发表时间：
2019-10-10
期刊：
影响因子：
64.8
通讯作者：
Bernards, Rene
中科院分区：
文献类型：
--
作者：
Wang, Cun;Vegna, Serena;Bernards, Rene
由于缺乏针对关键依赖性的药物，肝癌仍然难以治疗;广谱激酶抑制剂如索拉非尼仅为肝细胞癌患者提供适度的益处。衰老的诱导可以代表用于治疗癌症的策略，特别是当与选择性消除衰老癌细胞的第二种药物（衰老溶解）组合时。在这里，使用激酶组集中的遗传筛选，我们表明，药物抑制DNA复制激酶CDC 7诱导衰老选择性在肝癌细胞突变的TP 53。一项后续的化学筛选确定了抗抑郁药舍曲林作为一种药物，可以杀死因抑制CDC 7而衰老的肝细胞癌细胞。舍曲林抑制mTOR信号传导，靶向该通路的选择性药物在用CDC 7抑制剂处理的肝细胞癌细胞中引起凋亡性细胞死亡方面非常有效。mTOR信号传导在其抑制后的反馈再激活在已经用CDC 7抑制剂处理的细胞中被阻断，这导致mTOR的持续抑制和细胞死亡。使用多个体内肝癌小鼠模型，我们表明联合抑制CDC 7和mTOR的治疗导致肿瘤生长显著减少。我们的数据表明，利用诱导的脆弱性可能是肝癌的有效治疗方法。
Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies,; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis),. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations inTP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer.