2. Academic Validation
  3. Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

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

  • Science. 2024 Jun 7;384(6700):eadk0775. doi: 10.1126/science.adk0775.
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

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 5 Illumina, Inc., San Diego, CA 92121, USA.
  • 6 Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
  • 7 Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 8 Monoceros Biosystems LLC, San Diego, CA 92130, USA.
  • 9 Mirati Therapeutics, Inc., San Diego, CA 92121, USA.
  • 10 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 11 Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
  • 12 Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 13 Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  • 14 Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
PMID: 38843331 DOI: 10.1126/science.adk0775
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.

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