Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.
Science
; 384(6700): eadk0775, 2024 06 07.
Article
de 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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs du pancréas
/
Régulation de l'expression des gènes tumoraux
/
Protéines proto-oncogènes p21(ras)
/
Système de signalisation des MAP kinases
/
Carcinome du canal pancréatique
/
Extracellular Signal-Regulated MAP Kinases
/
Transcriptome
/
Mutation
Limites:
Animals
/
Humans
Langue:
En
Journal:
Sci. (N.Y., N.Y.)
/
Science
Année:
2024
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique
Pays de publication:
États-Unis d'Amérique