Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers.
Nat Commun
; 15(1): 5110, 2024 Jun 14.
Article
em En
| MEDLINE
| ID: mdl-38877018
ABSTRACT
Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Translocação Genética
/
Proteínas Tirosina Quinases
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Proteínas de Fusão Oncogênica
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Proteínas Proto-Oncogênicas c-ret
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Neoplasias
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article