@article {1287596, title = {Improved detection of synthetic lethal interactions in Drosophila cells using variable dose analysis (VDA)}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, number = {50}, year = {2017}, month = {2017 Dec 12}, pages = {E10755-E10762}, abstract = {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.}, issn = {1091-6490}, doi = {10.1073/pnas.1713362114}, author = {Housden, Benjamin E and Li, Zhongchi and Kelley, Colleen and Wang, Yuanli and Hu, Yanhui and Valvezan, Alexander J and Manning, Brendan D and Perrimon, Norbert} }