Multiscale mapping of transcriptomic signatures for cardiotoxic drugs.
Nat Commun
; 15(1): 7968, 2024 Sep 11.
Article
em En
| MEDLINE
| ID: mdl-39261481
ABSTRACT
Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines enables us to correctly reidentify a genomic variant causally linked to anthracycline-induced cardiotoxicity and predict genomic variants potentially associated with TKI-induced cardiotoxicity. We conclude that mRNA expression profiles when integrated with publicly available genomic, pathway, and single cell transcriptomic datasets, provide multiscale signatures for cardiotoxicity that could be used for drug development and patient stratification.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Perfilação da Expressão Gênica
/
Miócitos Cardíacos
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Inibidores de Proteínas Quinases
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Transcriptoma
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Cardiotoxicidade
Limite:
Humans
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2024
Tipo de documento:
Article