title: EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma.
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.
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Navas
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández-Porras
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Schuhmacher
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerra
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D000230:Adenocarcinoma; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D004847:Epithelial Cells; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016159:Tumor Suppressor Protein p53; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins