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Improved detection of synthetic lethal interactions in Drosophila cells using variable dose analysis (VDA)

Proceedings of the National Academy of Sciences of the United States of America, ISSN: 1091-6490, Vol: 114, Issue: 50, Page: E10755-E10762
2017
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Article Description

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.

Bibliographic Details

Housden, Benjamin E; Li, Zhongchi; Kelley, Colleen; Wang, Yuanli; Hu, Yanhui; Valvezan, Alexander J; Manning, Brendan D; Perrimon, Norbert

Proceedings of the National Academy of Sciences

Multidisciplinary

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