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Targeting ERK beyond the boundaries of the kinase active site in melanoma.
Sammons, Rachel M; Ghose, Ranajeet; Tsai, Kenneth Y; Dalby, Kevin N.
Afiliação
  • Sammons RM; Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas.
  • Ghose R; Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
  • Tsai KY; Department of Chemistry and Biochemistry, The City College of New York, New York, New York.
  • Dalby KN; Departments of Anatomic Pathology and Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Mol Carcinog ; 58(9): 1551-1570, 2019 09.
Article em En | MEDLINE | ID: mdl-31190430
Extracellular signal-regulated kinase 1/2 (ERK1/2) constitute a point of convergence for complex signaling events that regulate essential cellular processes, including proliferation and survival. As such, dysregulation of the ERK signaling pathway is prevalent in many cancers. In the case of BRAF-V600E mutant melanoma, ERK inhibition has emerged as a viable clinical approach to abrogate signaling through the ERK pathway, even in cases where MEK and Raf inhibitor treatments fail to induce tumor regression due to resistance mechanisms. Several ERK inhibitors that target the active site of ERK have reached clinical trials, however, many critical ERK interactions occur at other potentially druggable sites on the protein. Here we discuss the role of ERK signaling in cell fate, in driving melanoma, and in resistance mechanisms to current BRAF-V600E melanoma treatments. We explore targeting ERK via a distinct site of protein-protein interaction, known as the D-recruitment site (DRS), as an alternative or supplementary mode of ERK pathway inhibition in BRAF-V600E melanoma. Targeting the DRS with inhibitors in melanoma has the potential to not only disrupt the catalytic apparatus of ERK but also its noncatalytic functions, which have significant impacts on spatiotemporal signaling dynamics and cell fate.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Domínio Catalítico / Sistema de Sinalização das MAP Quinases / Inibidores de Proteínas Quinases / Melanoma Limite: Animals / Humans Idioma: En Revista: Mol Carcinog Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Domínio Catalítico / Sistema de Sinalização das MAP Quinases / Inibidores de Proteínas Quinases / Melanoma Limite: Animals / Humans Idioma: En Revista: Mol Carcinog Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2019 Tipo de documento: Article