Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF

Cancer Cell. 2019 Apr 15;35(4):573-587.e6. doi: 10.1016/j.ccell.2019.03.002. Epub 2019 Apr 8.

Abstract

Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.

Keywords: Cdk4; EGFR; Erlotinib; PDX tumor models; Pancreatic cancer; c-Raf; therapeutic mouse models; transcriptional profiles; tumor regression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / enzymology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Erlotinib Hydrochloride / pharmacology*
  • Gefitinib / pharmacology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Signal Transduction
  • Tumor Burden / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Xenograft Model Antitumor Assays

Substances

  • KRAS protein, human
  • Protein Kinase Inhibitors
  • TP53 protein, human
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • EGFR protein, mouse
  • ErbB Receptors
  • Proto-Oncogene Proteins c-raf
  • Raf1 protein, human
  • Raf1 protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Gefitinib