文章基本信息

标题：Improved detection of synthetic lethal interactions in Drosophila cells using variable dose analysis (VDA)
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作者：Benjamin E. Housden ; Zhongchi Li ; Colleen Kelley 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：50
页码：E10755-E10762
DOI：10.1073/pnas.1713362114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Synthetic sick or synthetic lethal (SS/L) screens are a powerful way to identify candidate drug targets to specifically kill tumor cells, but this approach generally suffers from low consistency between screens. We found that many SS/L interactions involve essential genes and are therefore detectable within a limited range of knockdown efficiency. Such interactions are often missed by overly efficient RNAi reagents. We therefore developed an assay that measures viability over a range of knockdown efficiency within a cell population. This method, called Variable Dose Analysis (VDA), is highly sensitive to viability phenotypes and reproducibly detects SS/L interactions. We applied the VDA method to search for SS/L interactions with TSC1 and TSC2 , the two tumor suppressors underlying tuberous sclerosis complex (TSC), and generated a SS/L network for TSC. Using this network, we identified four Food and Drug Administration-approved drugs that selectively affect viability of TSC-deficient cells, representing promising candidates for repurposing to treat TSC-related tumors.
关键词：synthetic lethality ; Drosophila ; RNAi ; high-throughput screening ; drug target discovery