Improved detection of synthetic lethal interactions in Drosophila cells using variable dose analysis (VDA).
Proc Natl Acad Sci U S A
; 114(50): E10755-E10762, 2017 12 12.
Article
en En
| MEDLINE
| ID: mdl-29183982
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Ensayos de Selección de Medicamentos Antitumorales
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Genes Supresores de Tumor
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Interferencia de ARN
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Drosophila
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Epistasis Genética
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Genes Letales
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Año:
2017
Tipo del documento:
Article