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
  • 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.

Products