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

María Teresa Blasco, Carolina Navas, Guillermo Martín-Serrano, Osvaldo Graña-Castro, Carmen G. Lechuga, Laura Martín-Díaz, Magdolna Djurec, Jing Li, Lucia Morales-Cacho, Laura Esteban-Burgos, Javier Perales-Patón, Emilie Bousquet-Mur, Eva Castellano, Harrys K.C. Jacob, Lavinia Cabras, Monica Musteanu, Matthias Drosten, Sagrario Ortega, Francisca Mulero, Bruno SainzNelson Dusetti, Juan Iovanna, Francisco Sánchez-Bueno, Manuel Hidalgo, Hossein Khiabanian, Raul Rabadán, Fátima Al-Shahrour, Carmen Guerra, Mariano Barbacid

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)573-587.e6
JournalCancer Cell
Volume35
Issue number4
DOIs
StatePublished - Apr 15 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Keywords

  • Cdk4
  • EGFR
  • Erlotinib
  • PDX tumor models
  • Pancreatic cancer
  • c-Raf
  • therapeutic mouse models
  • transcriptional profiles
  • tumor regression

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