Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Blood ; 122(9): 1599-609, 2013 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-23861246

RESUMO

Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre-B-cell ALL (B-ALL) cell lines and pediatric patient samples. Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs and led to transcriptional changes, including decreased expression of antiapoptotic PRKCB gene and increase in proapoptotic BAX and BBC3 genes. Further, Mer inhibition promoted chemosensitization, decreased colony-forming potential in clonogenic assays, and delayed disease onset in a mouse xenograft model of leukemia. Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy. This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction, thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL. Additionally, Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications.


Assuntos
Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , c-Mer Tirosina Quinase
2.
J Clin Invest ; 123(5): 2257-67, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23585477

RESUMO

Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that MERTK expression correlates with disease progression. MERTK expression was highest in metastatic melanomas, followed by primary melanomas, while the lowest expression was observed in nevi. Additionally, over half of melanoma cell lines overexpressed MERTK compared with normal human melanocytes; however, overexpression did not correlate with mutations in BRAF or RAS. Stimulation of melanoma cells with the MERTK ligand GAS6 resulted in the activation of several downstream signaling pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT. MERTK inhibition via shRNA reduced MERTK-mediated downstream signaling, reduced colony formation by up to 59%, and diminished tumor volume by 60% in a human melanoma murine xenograft model. Treatment of melanoma cells with UNC1062, a novel MERTK-selective small-molecule tyrosine kinase inhibitor, reduced activation of MERTK-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar, and inhibited invasion of melanoma cells. This work establishes MERTK as a therapeutic target in melanoma and provides a rationale for the continued development of MERTK-targeted therapies.


Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Melanócitos/metabolismo , Camundongos , Camundongos SCID , Microscopia de Fluorescência , Modelos Biológicos , Mutação , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Proto-Oncogene Mas , c-Mer Tirosina Quinase
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA