RT Journal Article SR Electronic T1 Variable dose analysis: A novel RNAi-based method for detection of synthetic lethal interactions JF bioRxiv FD Cold Spring Harbor Laboratory SP 176974 DO 10.1101/176974 A1 Benjamin E. Housden A1 Zhongchi Li A1 Colleen Kelley A1 Yuanli Wang A1 Yanhui Hu A1 Alexander J. Valvezan A1 Brendan D. Manning A1 Norbert Perrimon YR 2017 UL http://biorxiv.org/content/early/2017/08/16/176974.abstract AB Synthetic sick or synthetic lethal (SS/L) screens are a powerful way to identify candidate drug targets to specifically kill tumor cells but such screens generally suffer from low reproducibility. 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 FDA-approved drugs that selectively affect viability of TSC deficient cells, representing promising candidates for repurposing to treat TSC-related tumors.