dc.contributor.author | Housden, BE | |
dc.contributor.author | Li, Z | |
dc.contributor.author | Kelley, C | |
dc.contributor.author | Wang, Y | |
dc.contributor.author | Hu, Y | |
dc.contributor.author | Valvezan, AJ | |
dc.contributor.author | Manning, BD | |
dc.contributor.author | Perrimon, N | |
dc.date.accessioned | 2017-12-05T14:09:02Z | |
dc.date.issued | 2017-11-28 | |
dc.description.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. | en_GB |
dc.description.sponsorship | This work was supported by NIH Grant P01CA120964; University of Pennsylvania Orphan Disease Program Grant MDBR-15-103-LAM; and Department of Defense Grant W81XWH-16-1-0127. N.P. is a Howard Hughes Medical Institute Investigator. | en_GB |
dc.identifier.citation | Published online 28 November 2017 | en_GB |
dc.identifier.doi | 10.1073/pnas.1713362114 | |
dc.identifier.uri | http://hdl.handle.net/10871/30582 | |
dc.language.iso | en | en_GB |
dc.publisher | National Academy of Sciences | en_GB |
dc.relation.source | Data deposition: RNAi screen data are provided in Datasets S1–S6 and in the Drosophila RNAi Screening Center (DRSC) database and are publicly available at http://www.flyrnai.org/cgi-bin/RNAi_public_screen.pl?project_id=197 and http://www.flyrnai.org/cgi-bin/RNAi_public_screen.pl?project_id=210. | en_GB |
dc.rights | This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND): https://creativecommons.org/licenses/by-nc-nd/4.0/ | en_GB |
dc.subject | synthetic lethality | en_GB |
dc.subject | Drosophila | en_GB |
dc.subject | RNAi | en_GB |
dc.subject | high-throughput screening | en_GB |
dc.subject | drug target discovery | en_GB |
dc.title | Improved detection of synthetic lethal interactions in Drosophila cells using Variable Dose Analysis (VDA) | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2017-12-05T14:09:02Z | |
dc.identifier.issn | 0027-8424 | |
dc.description | This is the author accepted manuscript. The final version is available from National Academy of Sciences via the DOI in this record. | en_GB |
dc.identifier.journal | Proceedings of the National Academy of Sciences | en_GB |