荷兰癌症研究所René Bernards、Leila Akkari以及上海交通大学医学院附属仁济医院覃文新等研究人员合作开发了肝癌治疗的新策略。相关论文2019年10月2日在线发表于《自然》。
使用针对激酶组的遗传筛选，研究人员发现DNA复制激酶CDC7的药理学抑制选择性诱导TP53突变的肝癌细胞衰老。后续化学筛查确定抗抑郁药舍曲林为能够杀伤因为抑制CDC7而衰老的肝癌细胞的药物。舍曲林抑制mTOR信号传导，靶向该途径的选择性药物在引起用CDC7抑制剂治疗的肝癌细胞凋亡中非常有效。mTOR信号被抑制后的反馈再激活在已经用CDC7抑制剂处理过的细胞中被阻断，这导致mTOR的持续抑制和细胞死亡。
使用多种肝癌的体内小鼠模型，研究人员显示CDC7和mTOR联合抑制的治疗导致肿瘤生长明显降低。这些数据表明，利用诱发的弱点可能是治疗肝癌的有效方法。
据介绍，由于缺乏针对关键靶点的药物，肝癌仍然难以治疗。广谱激酶抑制剂（如索拉非尼）仅对肝细胞癌患者提供适度的获益。诱导衰老可能代表了一种治疗癌症的策略，尤其是与另外一种可以选择性消除衰老的癌细胞（衰老作用）药物结合使用时。
附：英文原文
Title: Inducing and exploiting vulnerabilities for the treatment of liver cancer
Author: Cun Wang, Serena Vegna, Haojie Jin, Bente Benedict, Cor Lieftink, Christel Ramirez, Rodrigo Leite de Oliveira, Ben Morris, Jules Gadiot, Wei Wang, Aime du Chatinier, Liqin Wang, Dongmei Gao, Bastiaan Evers, Guangzhi Jin, Zheng Xue, Arnout Schepers, Fleur Jochems, Antonio Mulero Sanchez, Sara Mainardi, Hein te Riele, Roderick L. Beijersbergen, Wenxin Qin, Leila Akkari, Ren Bernards
Issue&Volume: 2019-10-02
Abstract:
Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies1,2; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma3. 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)4,5. 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 in TP53. 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 inhibition6 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.
DOI: 10.1038/s41586-019-1607-3
Source:https://www.nature.com/articles/s41586-019-1607-3
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
