Housden, B.E., Li, Z., Kelley, C., Wang, Y., Hu, Y., Valvezan, A.J., Manning, B.D., Perrimon, N. (2017). Improved detection of synthetic lethal interactions in Drosophila cells using variable dose analysis (VDA).  Proc. Natl. Acad. Sci. U.S.A. 114(50): E10755--EE10762.

FBrf0237649

Research paper

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.

PMC5740648 (PMC) (EuropePMC)