Publication: Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.
dc.contributor.author | Blasco, María Teresa | |
dc.contributor.author | Navas, Carolina | |
dc.contributor.author | Martín-Serrano, Guillermo | |
dc.contributor.author | Martín-Díaz, Laura | |
dc.contributor.author | Li, Jing | |
dc.contributor.author | Morales-Cacho, Lucia | |
dc.contributor.author | Esteban-Burgos, Laura | |
dc.contributor.author | Perales-Patón, Javier | |
dc.contributor.author | Bousquet-Mur, Emilie | |
dc.contributor.author | Castellano, Eva | |
dc.contributor.author | Jacob, Harrys K C | |
dc.contributor.author | Cabras, Lavinia | |
dc.contributor.author | Sainz, Bruno | |
dc.contributor.author | Dusetti, Nelson | |
dc.contributor.author | Iovanna, Juan | |
dc.contributor.author | Sánchez-Bueno, Francisco | |
dc.contributor.author | Hidalgo, Manuel | |
dc.contributor.author | Khiabanian, Hossein | |
dc.contributor.author | Rabadán, Raul | |
dc.contributor.author | Graña Castro, Osvaldo | |
dc.contributor.author | Lechuga C, Lechuga CG | |
dc.contributor.author | Djurec M, Djurec M | |
dc.contributor.author | Musteanu, Mónica | |
dc.contributor.author | Drosten, Matthias | |
dc.contributor.author | Ortega Jimenez, Sagrario | |
dc.contributor.author | Mulero, Francisca | |
dc.contributor.author | Guerra, Carmen | |
dc.contributor.author | Barbacid, Mariano | |
dc.contributor.author | Al-Shahrour, Fatima | |
dc.contributor.funder | Unión Europea. Comisión Europea. European Research Council (ERC) | es_ES |
dc.contributor.funder | Unión Europea. Comisión Europea | es_ES |
dc.contributor.funder | Asociación Española Contra el Cáncer | es_ES |
dc.contributor.funder | Ligue Nationale Contre le Cancer (Francia) | es_ES |
dc.contributor.funder | United States Department of Health and Human Services | es_ES |
dc.contributor.funder | Deutsche Forschungsgemeinschaft (Alemania) | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Fundación La Caixa | es_ES |
dc.contributor.funder | Ministerio de Economía, Industria y Competitividad (España) | es_ES |
dc.contributor.funder | Fundación AXA | es_ES |
dc.date.accessioned | 2022-07-27T10:56:57Z | |
dc.date.available | 2022-07-27T10:56:57Z | |
dc.date.issued | 2019-04-15 | |
dc.description.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. | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.description.sponsorship | We thank B. Jimenez, M. San Roman, R. Villar, and S. Jimenez for excellent technical assistance; I. Aragon, A. Lopez, F. Diaz, and I. Blanco (Animal Facility) for mouse work; G. Visdomine, C. Penalba, and G. Garaulet (Molecular Imaging Unit) for ultrasound studies; P. Vargiu (Transgenic Unit) for help in generating the TetO-FlpO strain; N. Cabrera, A. de Martino (Histopathology Unit) and M. Morente (Tumor Bank) for histopathological analysis, and C. Blanco and A. Cebria (Experimental Therapeutics) for determining the IC50 values of gefinitib and erlotinib. Special thanks to J. de la Pena and E. Ortiz (Servicio de Anatomia Patologica HCUVA) and T. Escamez and V. Navarro (Biobanco-IMIM) for their help with the PDX tumor models, and to R. Nieto, J.M. Ligos, and M. Montoya (Cytometry Unit, CNIC) for fluorescence-activated cell sorting analysis of apoptotic cells. This work was supported by grants from the European Research Council (advanced grants ERC-AG/250297-RAS AHEAD and ERC-AG/695566-THERACAN), from the Spanish Ministry of Economy and Competitiveness (SAF2014-59864-R) to M.B. Additional support was also obtained from grants from the Asociacion Espanola contra el Cancer (GC16173694BARB) to M.B. and B.S., from La Ligue Contre le Cancer to J. I., from the European Research Council (advanced grants ERC-2014-ADG) to M.H., and from the NIH (U54CA193313 and U54CA209997) to R.R. M.T.B was supported by an FPU fellowship from the Spanish Ministry of Education. C.N. was supported by a Juan de la Cierva Award. M. Djurec was partially supported by a pre-doctoral fellowship from La Caixa. J.P.-P. was supported by a Severo Ochoa FPI fellowship from the Spanish Ministry of Economy and Competitiveness. M.B. is the recipient of an Endowed Chair from the AXA Research Fund. | es_ES |
dc.format.number | 4 | es_ES |
dc.format.page | 573-587.e6 | es_ES |
dc.format.volume | 35 | es_ES |
dc.identifier.citation | Cancer Cell . 2019;35(4):573-587.e6. | es_ES |
dc.identifier.doi | 10.1016/j.ccell.2019.03.002 | es_ES |
dc.identifier.e-issn | 1878-3686 | es_ES |
dc.identifier.journal | Cancer cell | es_ES |
dc.identifier.pubmedID | 30975481 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/14772 | |
dc.language.iso | eng | es_ES |
dc.publisher | Cell Press | es_ES |
dc.relation.projectFIS | info:eu-repo/grantAgreement/ES/SAF2014-59864-R | es_ES |
dc.relation.projectFIS | info:eu-repo/grantAgreement/ES/GC16173694BARB | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/FP7/250297/EU | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/H2020/695566/EU | es_ES |
dc.relation.publisherversion | https://doi.org/ 10.1016/j.ccell.2019.03.002. | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Oncología Experimental | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Apoptosis | es_ES |
dc.subject.mesh | Carcinoma, Pancreatic Ductal | es_ES |
dc.subject.mesh | Cell Line, Tumor | es_ES |
dc.subject.mesh | Cell Proliferation | es_ES |
dc.subject.mesh | ErbB Receptors | es_ES |
dc.subject.mesh | Erlotinib Hydrochloride | es_ES |
dc.subject.mesh | Gefitinib | es_ES |
dc.subject.mesh | Gene Expression Regulation, Neoplastic | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Mice, 129 Strain | es_ES |
dc.subject.mesh | Mice, Inbred C57BL | es_ES |
dc.subject.mesh | Mice, Transgenic | es_ES |
dc.subject.mesh | Mutation | es_ES |
dc.subject.mesh | Pancreatic Neoplasms | es_ES |
dc.subject.mesh | Protein Kinase Inhibitors | es_ES |
dc.subject.mesh | Proto-Oncogene Proteins c-raf | es_ES |
dc.subject.mesh | Proto-Oncogene Proteins p21(ras) | es_ES |
dc.subject.mesh | Signal Transduction | es_ES |
dc.subject.mesh | Tumor Burden | es_ES |
dc.subject.mesh | Tumor Suppressor Protein p53 | es_ES |
dc.subject.mesh | Xenograft Model Antitumor Assays | es_ES |
dc.title | Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF. | es_ES |
dc.type | journal article | es_ES |
dc.type.hasVersion | VoR | es_ES |
dspace.entity.type | Publication |
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