CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Cancer Res. 2019 Nov 15;79(22):5693-5698. doi: 10.1158/0008-5472.CAN-19-1364. Epub 2019 Aug 6.
Kinases are signaling enzymes that regulate diverse cellular processes. As such, they are frequently mutated in cancer and therefore represent important targets for drug discovery. However, until recently, systematic approaches to identify vulnerabilities and resistances of kinases to DNA-damaging chemotherapeutics have not been possible, partially due to the lack of appropriate technologies. With the advent of CRISPR-Cas9, a comprehensive study has investigated the cellular survival of more than 300 kinase-deficient isogenic cell lines to a diverse panel of DNA-damaging agents, enriched for chemotherapeutics. Here, we discuss how this approach has allowed for the rational development of combination therapies that are aimed at using synthetic lethal interactions between kinase deficiencies and DNA-damaging agents that are used as chemotherapeutics.
激酶是信号酶，可调节多种细胞过程。因此，它们在癌症中经常发生突变，因此是药物发现的重要靶标。然而，直到最近，还不可能采用系统的方法来确定激酶对 DNA 损伤化疗药物的易损性和耐药性，部分原因是缺乏适当的技术。随着 CRISPR-Cas9 的出现，一项全面的研究调查了 300 多种激酶缺陷同基因细胞系对多种 DNA 损伤剂（富含化疗药物）的细胞存活情况。在这里，我们将讨论这种方法如何允许合理开发旨在利用激酶缺陷与用作化疗药物的 DNA 损伤剂之间的合成致死相互作用的联合疗法。
