RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics.
J Clin Invest
; 131(22)2021 11 15.
Article
em En
| MEDLINE
| ID: mdl-34554931
ABSTRACT
Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Bexiga Urinária
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Amplificação de Genes
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Proteínas Proto-Oncogênicas c-raf
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Quinases de Proteína Quinase Ativadas por Mitógeno
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article