Accurate Drug Repositioning through Non-tissue-Specific Core Signatures from Cancer Transcriptomes.
Cell Rep
; 25(2): 523-535.e5, 2018 10 09.
Article
en En
| MEDLINE
| ID: mdl-30304690
ABSTRACT
Experimental large-scale screens for drug repositioning are limited by restriction to in vitro conditions and lack of applicability to real human conditions. Here, we developed an in silico screen in human in vivo conditions using a reference of single gene mutations' non-tissue-specific "core transcriptome signatures" (CSs) of 8,476 genes generated from the TCGA database. We developed the core-signature drug-to-gene (csD2G) software to scan 3,546 drug treatment profiles against the reference signatures. csD2G significantly outperformed conventional cell line-based gene perturbation signatures and existing drug-repositioning methods in both coverage and specificity. We highlight this with 3 demonstrated applications (1) repositioned category of psychiatric drugs to inhibit the TGF-ß pathway; (2) antihypertensive calcium channel blockers predicted to activate AMPK and inhibit AKT pathways, and validated by clinical electronic medical records; and (3) 7 drugs predicted and validated to selectively target the AKT-FOXO and AMPK pathways and thus regulate worm lifespan.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Regulación Neoplásica de la Expresión Génica
/
Bases de Datos Factuales
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Biología Computacional
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Reposicionamiento de Medicamentos
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Transcriptoma
/
Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Rep
Año:
2018
Tipo del documento:
Article