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Sci Rep ; 9(1): 18630, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31819100


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.

Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Estaurosporina/análogos & derivados , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Animais , Antígenos CD34/genética , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , MAP Quinase Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase Quinase 1/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Pessoa de Meia-Idade , Estaurosporina/administração & dosagem
Nat Commun ; 9(1): 3501, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158526


Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, we use high-throughput phosphoproteomics to build a functional TNBC taxonomy. A cluster of 159 phosphosites is upregulated in relapsed cases of a training set (n = 34 patients), with 11 hyperactive kinases accounting for this phosphoprofile. A mass-spectrometry-to-immunohistochemistry translation step, assessing 2 independent validation sets, reveals 6 kinases with preserved independent prognostic value. The kinases split the validation set into two patterns: one without hyperactive kinases being associated with a >90% relapse-free rate, and the other one showing ≥1 hyperactive kinase and being associated with an up to 9.5-fold higher relapse risk. Each kinase pattern encompasses different mutational patterns, simplifying mutation-based taxonomy. Drug regimens designed based on these 6 kinases show promising antitumour activity in TNBC cell lines and patient-derived xenografts. In summary, the present study elucidates phosphosites and kinases implicated in TNBC and suggests a target-based clinical classification system for TNBC.

Fosfoproteínas/metabolismo , Fosfotransferases/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Espectrometria de Massas , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/mortalidade
J Health Care Poor Underserved ; 27(4): 1656-1673, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27818430


The aim of this study is to explore what actual guidance is provided by authoritative ethics documents regarding the recognition and protection of the vulnerable. The documents included in this analysis are the Belmont Report, the Declaration of Helsinki, The Council for International Organizations of Medical Sciences (CIOMS) Guidelines, and the UNESCO Universal Declaration on Bioethics and Human Rights, including its supplementary report on vulnerability. A qualitative analysis of these documents was conducted in light of three questions: what is vulnerability, who are the vulnerable, and how should the vulnerable be protected? The results show significant differences among the documents regarding the first two questions. None of the documents provides any guidance on the third question (how to protect the vulnerable). These results suggest a great discrepancy between the acknowledged importance of the concept of vulnerability and a general understanding of the scope, content, and practical implications of vulnerability.

Bioética , Direitos Humanos , Pesquisa Qualitativa , Humanos , Nações Unidas
Cell Rep ; 15(12): 2705-18, 2016 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-27292634


Epithelial malignancies are effectively treated by antiangiogenics; however, acquired resistance is a major problem in cancer therapeutics. Epithelial tumors commonly have mutations in the MAPK/Pi3K-AKT pathways, which leads to high-rate aerobic glycolysis. Here, we show how multikinase inhibitor antiangiogenics (TKIs) induce hypoxia correction in spontaneous breast and lung tumor models. When this happens, the tumors downregulate glycolysis and switch to long-term reliance on mitochondrial respiration. A transcriptomic, metabolomic, and phosphoproteomic study revealed that this metabolic switch is mediated by downregulation of HIF1α and AKT and upregulation of AMPK, allowing uptake and degradation of fatty acids and ketone bodies. The switch renders mitochondrial respiration necessary for tumor survival. Agents like phenformin or ME344 induce synergistic tumor control when combined with TKIs, leading to metabolic synthetic lethality. Our study uncovers mechanistic insights in the process of tumor resistance to TKIs and may have clinical applicability.

Inibidores da Angiogênese/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Ácidos Graxos/metabolismo , Feminino , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Corpos Cetônicos/metabolismo , Metaboloma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Neoplasias/patologia , Oxigênio/metabolismo , Compostos de Fenilureia/farmacologia , Fosfoproteínas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos