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MERTK receptor tyrosine kinase is a therapeutic target in melanoma.
J Clin Invest ; 123(5): 2257-67, 2013 May.
Article em En | MEDLINE | ID: mdl-23585477
ABSTRACT
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

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Regulação Neoplásica da Expressão Gênica / Proteínas Proto-Oncogênicas / Receptores Proteína Tirosina Quinases / Melanoma Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: J Clin Invest Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Regulação Neoplásica da Expressão Gênica / Proteínas Proto-Oncogênicas / Receptores Proteína Tirosina Quinases / Melanoma Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: J Clin Invest Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Estados Unidos