Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.
Science
; 384(6700): eadk0775, 2024 06 07.
Article
em En
| MEDLINE
| ID: mdl-38843331
ABSTRACT
How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
/
Regulação Neoplásica da Expressão Gênica
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Proteínas Proto-Oncogênicas p21(ras)
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Sistema de Sinalização das MAP Quinases
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Carcinoma Ductal Pancreático
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MAP Quinases Reguladas por Sinal Extracelular
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Transcriptoma
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Mutação
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos