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

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


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.

MeSH terms

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


  • Extracellular Signal-Regulated MAP Kinases
  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)