A high-throughput siRNA screening platform to identify MYC-synthetic lethal genes as candidate therapeutic targets.
A high-throughput siRNA screening platform to identify MYC-synthetic lethal genes as candidate therapeutic targets.
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DOI：
10.1007/978-1-62703-429-6_12
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发表时间：
2013
影响因子：
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通讯作者：
C. Grandori
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文献类型：
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作者：
C. Grandori
针对特定基因和途径的靶向治疗代表了肿瘤治疗的未来。然而，几个常见的癌基因，如MYC，已被证明很难被药理学药物靶向。为了拓宽潜在的药物治疗靶点的菜单，我们描述了一种检测MYC过度表达细胞生存所必需的基因的方法，我们将其称为MYC合成致死基因(MYC-SL)(Toyota oshima等人，Proc Natl Acad Sci USA 109：9545-9550,2012)。这些基因代表了用于MYC驱动的癌症的药物开发的候选靶点，以及加深我们对MYC驱动的肿瘤发生生物学的理解的探针。该发现平台包括以下组件：(1)能够在没有癌基因诱导的衰老(OIS)反应的情况下过度表达MYC的等基因细胞系统(Benanti和Gloway，Mol Cell Biol 24：2842-2852,2004；Benanti等，Mol Cancer RES 5：1181-1189,2007)；(2)针对单个基因的阵列siRNA文库；(3)用于细胞分配、siRNA和读出分析的自动化实验室设备；以及(4)生物信息学和用于数据挖掘和可视化的软件。这一灵活的平台可以很容易地应用于其他癌基因或肿瘤抑制基因。
Targeted therapeutics toward specific genes and pathways represent the future of oncological treatments. However, several commonly activated oncogenes, such as MYC, have proven difficult to target by pharmacological agents. To broaden the menu of potentially druggable therapeutic targets, we describe a method to detect genes essential for the survival of MYC overexpressing cells, which we will refer to as MYC-synthetic lethal genes (MYC-SL) (Toyoshima et al., Proc Natl Acad Sci USA 109:9545–9550, 2012). These genes represent candidate targets for drug development to be utilized for MYC-driven cancers as well as probes to further our understanding of the biology of MYC-driven tumorigenesis. The discovery platform includes the following components: (1) an isogenic cell system that enables overexpression of MYC without oncogene-induced senescence (OIS) response (Benanti and Galloway, Mol Cell Biol 24:2842–2852, 2004; Benanti et al., Mol Cancer Res 5:1181–1189, 2007); (2) arrayed siRNA libraries targeting individual genes; (3) automated laboratory equipment for dispensing of cells, siRNAs, and readout assays; and (4) bioinformatics and software for data mining and visualization. This flexible platform can be readily applied to other oncogenes or tumor suppressor genes.