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

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 mutatio...

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Bibliographic Details
Authors: Blasco, María Teresa, Navas, Carolina, Martín-Serrano, Guillermo, Martín-Díaz, Laura, Li, Jing, Morales-Cacho, Lucia, Esteban-Burgos, Laura, Perales-Patón, Javier, Bousquet-Mur, Emilie, Castellano, Eva, Jacob, Harrys K C, Cabras, Lavinia, Sainz, Bruno, Dusetti, Nelson, Iovanna, Juan, Sánchez-Bueno, Francisco, Hidalgo, Manuel, Khiabanian, Hossein, Rabadán, Raul, Graña Castro, Osvaldo, Lechuga C, Lechuga CG, Djurec M, Djurec M, Musteanu, Mónica, Drosten, Matthias, Ortega Jimenez, Sagrario, Mulero, Francisca, Guerra, Carmen, Barbacid, Mariano, Al-Shahrour, Fatima
Format: article
Publication Date:2019
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/14772
Online Access:http://hdl.handle.net/20.500.12105/14772
Access Level:Open access
Keyword:Animals
Apoptosis
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Cell Proliferation
ErbB Receptors
Erlotinib Hydrochloride
Gefitinib
Gene Expression Regulation, Neoplastic
Humans
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Pancreatic Neoplasms
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-raf
Proto-Oncogene Proteins p21(ras)
Signal Transduction
Tumor Burden
Tumor Suppressor Protein p53
Xenograft Model Antitumor Assays
Description
Summary: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.

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