Multi-omics analysis delineates resistance mechanisms associated with BRAF inhibition in melanoma cells.
Exp Cell Res
; 442(1): 114215, 2024 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-39182666
ABSTRACT
Mutant BRAF is a critical oncogenic driver in melanoma, making it an attractive therapeutic target. However, the success of targeted therapy using BRAF inhibitors vemurafenib and dabrafenib has been limited due to development of resistance, restricting their clinical efficacy. A prior knowledge of resistance mechanisms to BRAFi or any cancer drug can lead to development of drugs that overcome resistance thus improving clinical outcomes. In vitro cellular models are powerful systems that can be utilized to mimic and study resistance mechanisms. In this study, we employed a multi-omics approach to characterize a panel of BRAF mutant melanoma cell lines to develop and systematically characterize BRAFi persister and resistant cells using exome sequencing, proteomics and phosphoproteomics. Our datasets revealed frequently observed intrinsic and acquired, genetic and non-genetic mechanisms of BRAFi resistance that have been studied in patients who developed resistance. In addition, we identified proteins that can be potentially targeted to overcome BRAFi resistance. Overall, we demonstrate that in vitro systems can be utilized not only to predict resistance mechanisms but also to identify putative therapeutic targets.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
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Tipos_de_cancer
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Pele
Base de dados:
MEDLINE
Assunto principal:
Resistencia a Medicamentos Antineoplásicos
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Proteômica
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Proteínas Proto-Oncogênicas B-raf
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Inibidores de Proteínas Quinases
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Melanoma
Limite:
Humans
Idioma:
En
Revista:
Exp Cell Res
Ano de publicação:
2024
Tipo de documento:
Article