EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma

Cancer Cell. 2012 Sep 11;22(3):318-30. doi: 10.1016/j.ccr.2012.08.001.

Abstract

Clinical evidence indicates that mutation/activation of EGF receptors (EGFRs) is mutually exclusive with the presence of K-RAS oncogenes in lung and colon tumors. We have validated these observations using genetically engineered mouse models. However, development of pancreatic ductal adenocarcinomas driven by K-Ras oncogenes are totally dependent on EGFR signaling. Similar results were obtained using human pancreatic tumor cell lines. EGFRs were also essential even in the context of pancreatic injury and absence of p16Ink4a/p19Arf. Only loss of p53 made pancreatic tumors independent of EGFR signaling. Additional inhibition of PI3K and STAT3 effectively prevented proliferation of explants derived from these p53-defective pancreatic tumors. These findings may provide the bases for more rational approaches to treat pancreatic tumors in the clinic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma
  • Animals
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Epithelial Cells
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Erlotinib Hydrochloride
  • Genes, ras*
  • Humans
  • Mice
  • Mice, Transgenic
  • Pancreas / metabolism
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • STAT3 Transcription Factor / antagonists & inhibitors
  • Signal Transduction*
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology
  • ras Proteins / genetics

Substances

  • KRAS protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Quinazolines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tumor Suppressor Protein p53
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins