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

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dc.contributor.authorBlasco, María Teresa
dc.contributor.authorNavas, Carolina
dc.contributor.authorMartín-Serrano, Guillermo
dc.contributor.authorMartín-Díaz, Laura
dc.contributor.authorLi, Jing
dc.contributor.authorMorales-Cacho, Lucia
dc.contributor.authorEsteban-Burgos, Laura
dc.contributor.authorPerales-Patón, Javier
dc.contributor.authorBousquet-Mur, Emilie
dc.contributor.authorCastellano, Eva
dc.contributor.authorJacob, Harrys K C
dc.contributor.authorCabras, Lavinia
dc.contributor.authorSainz, Bruno
dc.contributor.authorDusetti, Nelson
dc.contributor.authorIovanna, Juan
dc.contributor.authorSánchez-Bueno, Francisco
dc.contributor.authorHidalgo, Manuel
dc.contributor.authorKhiabanian, Hossein
dc.contributor.authorRabadán, Raul
dc.contributor.authorGraña Castro, Osvaldo
dc.contributor.authorLechuga C, Lechuga CG
dc.contributor.authorDjurec M, Djurec M
dc.contributor.authorMusteanu, Mónica
dc.contributor.authorDrosten, Matthias
dc.contributor.authorOrtega Jimenez, Sagrario
dc.contributor.authorMulero, Francisca
dc.contributor.authorGuerra, Carmen
dc.contributor.authorBarbacid, Mariano
dc.contributor.authorAl-Shahrour, Fatima
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC)
dc.contributor.funderUnión Europea. Comisión Europea
dc.contributor.funderAsociación Española Contra el Cáncer
dc.contributor.funderLigue Nationale Contre le Cancer (Francia)
dc.contributor.funderUnited States Department of Health and Human Services
dc.contributor.funderDeutsche Forschungsgemeinschaft (Alemania)
dc.contributor.funderMinisterio de Ciencia e Innovación (España)
dc.contributor.funderFundación La Caixa
dc.contributor.funderMinisterio de Economía, Industria y Competitividad (España)
dc.contributor.funderFundación AXA
dc.date.accessioned2022-07-27T10:56:57Z
dc.date.available2022-07-27T10:56:57Z
dc.date.issued2019-04-15
dc.description.abstractFive-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.peerreviewedSíes_ES
dc.description.sponsorshipWe 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.number4es_ES
dc.format.page573-587.e6es_ES
dc.format.volume35es_ES
dc.identifier.citationCancer Cell . 2019;35(4):573-587.e6.es_ES
dc.identifier.doi10.1016/j.ccell.2019.03.002es_ES
dc.identifier.e-issn1878-3686es_ES
dc.identifier.journalCancer celles_ES
dc.identifier.pubmedID30975481es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/14772
dc.language.isoenges_ES
dc.publisherCell Press
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/SAF2014-59864-Res_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/GC16173694BARBes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/250297/EUes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/695566/EUes_ES
dc.relation.publisherversionhttps://doi.org/ 10.1016/j.ccell.2019.03.002.es_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Oncología Experimentales_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalses_ES
dc.subject.meshApoptosises_ES
dc.subject.meshCarcinoma, Pancreatic Ductales_ES
dc.subject.meshCell Line, Tumores_ES
dc.subject.meshCell Proliferationes_ES
dc.subject.meshErbB Receptorses_ES
dc.subject.meshErlotinib Hydrochloridees_ES
dc.subject.meshGefitinibes_ES
dc.subject.meshGene Expression Regulation, Neoplastices_ES
dc.subject.meshHumanses_ES
dc.subject.meshMice, 129 Straines_ES
dc.subject.meshMice, Inbred C57BLes_ES
dc.subject.meshMice, Transgenices_ES
dc.subject.meshMutationes_ES
dc.subject.meshPancreatic Neoplasmses_ES
dc.subject.meshProtein Kinase Inhibitorses_ES
dc.subject.meshProto-Oncogene Proteins c-rafes_ES
dc.subject.meshProto-Oncogene Proteins p21(ras)es_ES
dc.subject.meshSignal Transductiones_ES
dc.subject.meshTumor Burdenes_ES
dc.subject.meshTumor Suppressor Protein p53es_ES
dc.subject.meshXenograft Model Antitumor Assayses_ES
dc.titleComplete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.es_ES
dc.typejournal articlees_ES
dc.type.hasVersionVoRes_ES
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