Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jun 7;384(6700):eadk0775.
doi: 10.1126/science.adk0775. Epub 2024 Jun 7.

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

Jeffrey A Klomp  1   2 , Jennifer E Klomp  1 , Clint A Stalnecker  1   2 , Kirsten L Bryant  1   2 , A Cole Edwards  3 , Kristina Drizyte-Miller  1 , Priya S Hibshman  3 , J Nathaniel Diehl  4 , Ye S Lee  2 , Alexis J Morales  1 , Khalilah E Taylor  1 , Sen Peng  5 , Nhan L Tran  6 , Laura E Herring  7 , Alex W Prevatte  7 , Natalie K Barker  7 , Laura D Hover  8 , Jill Hallin  9 , Saikat Chowdhury  10 , Oluwadara Coker  10 , Hey Min Lee  10 , Craig M Goodwin  1 , Prson Gautam  11 , Peter Olson  9 , James G Christensen  9 , John P Shen  10 , Scott Kopetz  10 , Lee M Graves  1   2 , Kian-Huat Lim  12 , Andrea Wang-Gillam  12 , Krister Wennerberg  11   13 , Adrienne D Cox  1   2   3   14 , Channing J Der  1   2   3   4
Affiliations

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

Jeffrey A Klomp et al. Science. .

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.

PubMed Disclaimer

Similar articles

See all similar articles

MeSH terms

Substances

LinkOut - more resources