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dc.contributor.authorMorales, María Luz
dc.contributor.authorArenas, Alicia
dc.contributor.authorOrtiz-Ruiz, Alejandra
dc.contributor.authorLeivas, Alejandra
dc.contributor.authorRapado, Inmaculada
dc.contributor.authorRodríguez-García, Alba
dc.contributor.authorCastro, Nerea
dc.contributor.authorZagorac, Ivana 
dc.contributor.authorQuintela Fandino, Miguel Angel 
dc.contributor.authorGómez-López, Gonzalo 
dc.contributor.authorGallardo, Miguel
dc.contributor.authorAyala, Rosa
dc.contributor.authorLinares, María
dc.contributor.authorMartinez-Lopez, Joaquin
dc.identifier.citationSci Rep. 2019 ;9(1):18630.es_ES
dc.description.abstractFMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML.es_ES
dc.description.sponsorshipWe are particularly indebted to all the patients who participated in the study. This work was supported by the Instituto de Salud Carlos III (PI13/02378 and PI16/01530) and the CRIS foundation. M.L. had a postdoctoral fellowship from the Spanish Ministry of Economy and Competitiveness (FPDI-2013-016409) and holds a grant from the Spanish Society of Hematology and Hemotherapy.es_ES
dc.publisherNature Publishing Group es_ES
dc.titleMEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemiaes_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderCRIS Foundation
dc.contributor.funderSociedad Española de Hematología y Hemoterapia 
dc.identifier.journalScientific reportses_ES
dc.repisalud.orgCNIOCNIO::Unidades técnicas::Unidad de Investigación Clínica de Tumores Hematológicos H12O-CNIOes_ES
dc.rights.accessRightsopen accesses_ES

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