Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/14772
Title
Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.
Author(s)
Blasco, María Teresa | Navas, Carolina | Martín-Serrano, Guillermo | Martín-Díaz, Laura | Li, Jing | Morales-Cacho, Lucia | Esteban-Burgos, Laura CNIO | 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 CNIO | Khiabanian, Hossein | Rabadán, Raul | Graña Castro, Osvaldo CNIO | Lechuga C, Lechuga CG CNIO | Djurec M, Djurec M CNIO | Musteanu, Mónica CNIO | Drosten, Matthias CNIO | Ortega Jimenez, Sagrario CNIO | Mulero, Francisca CNIO | Guerra, Carmen CNIO | Barbacid, Mariano CNIO | Al-Shahrour, Fatima CNIO
Date issued
2019-04-15
Citation
Cancer Cell . 2019;35(4):573-587.e6.
Language
Inglés
Document type
journal article
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.
MESH
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
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