Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.
Science
; 384(6700): eadk0775, 2024 06 07.
Article
in 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pancreatic Neoplasms
/
Gene Expression Regulation, Neoplastic
/
Proto-Oncogene Proteins p21(ras)
/
MAP Kinase Signaling System
/
Carcinoma, Pancreatic Ductal
/
Extracellular Signal-Regulated MAP Kinases
/
Transcriptome
/
Mutation
Limits:
Animals
/
Humans
Language:
En
Journal:
Science
Year:
2024
Type:
Article
Affiliation country:
United States