Department of Radiation Oncology, University of California, San Francisco, California 94143-1331, USA.
Nat Rev Drug Discov. 2011 May;10(5):351-64. doi: 10.1038/nrd3374.
Unique features of tumours that can be exploited by targeted therapies are a key focus of current cancer research. One such approach is known as synthetic lethality screening, which involves searching for genetic interactions of two mutations whereby the presence of either mutation alone has no effect on cell viability but the combination of the two mutations results in cell death. The presence of one of these mutations in cancer cells but not in normal cells can therefore create opportunities to selectively kill cancer cells by mimicking the effect of the second genetic mutation with targeted therapy. Here, we summarize strategies that can be used to identify synthetic lethal interactions for anticancer drug discovery, describe examples of such interactions that are currently being investigated in preclinical and clinical studies of targeted anticancer therapies, and discuss the challenges of realizing the full potential of such therapies.
肿瘤的独特特征可以被靶向治疗所利用，这是当前癌症研究的一个重点。一种这样的方法被称为合成致死筛选，它涉及到寻找两种突变的遗传相互作用，其中单独存在任何一种突变对细胞活力都没有影响，但两种突变的组合会导致细胞死亡。因此，在癌细胞中存在一种这种突变，而在正常细胞中不存在这种突变，可以创造机会，通过用靶向治疗模拟第二种遗传突变的效果，选择性地杀死癌细胞。在这里，我们总结了可用于鉴定抗癌药物发现中的合成致死相互作用的策略，描述了目前在靶向抗癌治疗的临床前和临床研究中正在研究的这些相互作用的例子，并讨论了实现这些治疗方法的全部潜力所面临的挑战。
