Faculty, Staff and Student Publications

Publication Date

6-7-2024

Journal

Science

DOI

10.1126/science.adk0775

PMID

38843331

PMCID

PMC11301402

PubMedCentral® Posted Date

8-6-2024

PubMedCentral® Full Text Version

Author MSS

Abstract

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and 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 significantly 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 and other components of the cell cycle machinery as key processes driving PDAC growth. In summary, these findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

Keywords

Animals, Humans, Mice, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Drug Resistance, Neoplasm, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Neoplastic, MAP Kinase Signaling System, Mutation, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Transcriptome, HEK293 Cells

Comments

This article has been corrected. See Science. 2024 Aug 22;385(6711):eads4435.

Published Open-Access

yes

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