Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers
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.
Authors
- Jennifer E. Klomp (ORCID: https://orcid.org/0000-0003-1781-648X)
- A. Cole Edwards (ORCID: https://orcid.org/0000-0001-9220-9642)
- Clint A. Stalnecker (ORCID: https://orcid.org/0000-0002-0570-4416)
- Adrienne D. Cox (ORCID: https://orcid.org/0000-0002-4901-2454)
- Ye S. Lee (ORCID: https://orcid.org/0000-0001-9026-6192)
- Scott Kopetz (ORCID: https://orcid.org/0000-0001-9647-3416)
- John Paul Shen (ORCID: https://orcid.org/0000-0003-4588-2775)
- Andrea Wang‐Gillam (ORCID: https://orcid.org/0000-0003-0458-7614)
- Jill Hallin (ORCID: https://orcid.org/0000-0002-8443-7116)
- Laura D. Hover (ORCID: https://orcid.org/0009-0007-2106-8679)
- Kristina Drizyte‐Miller (ORCID: https://orcid.org/0000-0001-7049-2934)
- Nhan L. Tran (ORCID: https://orcid.org/0000-0003-0908-9964)
- Saikat Chowdhury (ORCID: https://orcid.org/0000-0002-0783-3959)
- Natalie K. Barker (ORCID: https://orcid.org/0000-0001-9248-2710)
- Hey Min Lee (ORCID: https://orcid.org/0000-0001-7792-4226)
- Peter Olson (ORCID: https://orcid.org/0009-0008-5164-8102)
- Priya S. Hibshman
- Laura E. Herring (ORCID: https://orcid.org/0000-0003-4496-7312)
- Alex W. Prevatte
- Craig M. Goodwin (ORCID: https://orcid.org/0000-0003-1293-2334)
- Jeffrey A. Klomp (ORCID: https://orcid.org/0000-0002-5243-6987)
- Channing J. Der (ORCID: https://orcid.org/0000-0002-7751-2747)
- Krister Wennerberg (ORCID: https://orcid.org/0000-0002-1352-4220)
- Khalilah E. Taylor (ORCID: https://orcid.org/0009-0003-2136-2713)
- James G. Christensen (ORCID: https://orcid.org/0000-0003-1835-0335)
- Kirsten L. Bryant (ORCID: https://orcid.org/0000-0003-4026-0942)
- Kian‐Huat Lim (ORCID: https://orcid.org/0000-0002-2766-200X)
- Alexis Jean Morales (ORCID: https://orcid.org/0009-0002-3711-934X)
- Oluwadara Coker (ORCID: https://orcid.org/0000-0003-0504-2747)
- J. Nathaniel Diehl (ORCID: https://orcid.org/0000-0002-7309-0903)
- Lee M. Graves (ORCID: https://orcid.org/0000-0002-4736-9855)
- Prson Gautam (ORCID: https://orcid.org/0000-0002-1154-8501)
- Sen Peng
Institutions
- University of North Carolina at Chapel Hill (US)
Publication Details
- Journal
- UNC Libraries
- Published
- 2024-09-04
- DOI
- https://doi.org/10.17615/84ya-pd57
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Pancreatic Cancer Action Network
- Revolution Medicines
- University of Texas MD Anderson Cancer Center
- National Cancer Institute
- National Institute of General Medical Sciences
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill