MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia
EntityUAM. Departamento de Bioquímica
10.1038/s41598-019-54901-9Scientific Reports volume 9 (2019): 18630
Funded byThis 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
ProjectGobierno de España. PI13/02378; Gobierno de España. PI16/01530
SubjectsCancer therapeutic resistence; Targeted therapies; Trasnational research; Medicina
Rights© 2019 The Authors
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
FMS-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.
Google Scholar:Morales, María Luz - Arenas, Alicia - Ortiz-Ruiz, Alejandra - Leivas, Alejandra - Rapado, Inmaculada - Ortiz-Ruiz, Alba - Castro, Nerea - Zagorac, Ivana - Quintela Fandiño, Miguel Ángel - Gómez López, Gonzalo - Gallardo, Miguel - Ayala, Rosa - Linares, María - Martínez-López, Joaquín
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