Abstract
The majority of human melanomas harbor activating mutations of either N-RAS or its downstream effector B-RAF, which cause activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase and the ERK MAPK cascade. The melanoma-relevant effectors of ERK activation, however, are largely unknown. In this work, we show that increased ERK activation correlates strongly with mutational status of N-RAS or B-RAF in 21 melanoma cell lines. Melanoma lines that were wild-type for RAS/RAF showed low levels of ERK activation comparable with primary human melanocytes. Through supervised analysis of RNA expression profiles, we identified 82 genes, including TWIST1, HIF1alpha, and IL-8, which correlated with ERK activation across the panel of cell lines and which decreased with pharmacologic inhibition of ERK activity, suggesting that they are ERK transcriptional targets in melanoma. Additionally, lines lacking mutations of N-RAS and B-RAF were molecularly distinct and characterized by p53 inactivation, reduced ERK activity, and increased expression of epithelial markers. Analysis of primary human melanomas by tissue microarray confirmed a high correlation among expression of these epithelial markers in a heterogeneous sample of 570 primary human tumors, suggesting that a significant frequency of primary melanomas is of this "epithelial-like" subtype. These results show a molecularly distinct melanoma subtype that does not require ERK activation or epithelial-mesenchymal transformation for progression.
Highlights
Advanced melanoma is one of the most intractable entities of medical oncology
RAS engages multiple downstream effectors [e.g., RAF, phosphatidylinositol 3-kinase (PI3K), and Ral guanine nucleotide exchange factors; ref. 4] that can contribute to oncogenesis, the finding that N-RAS and B-RAF mutations are mutually exclusive in melanoma has prompted the notion that RAF mediates much of the transforming activity of RAS activation in this tumor type
Total extracellular signal-regulated kinase (ERK) and AKT levels were comparable in all lines, the cell lines were markedly heterogeneous with regard to steady-state phosphorylated ERK (pERK) and phosphorylated AKT (pAKT) levels
Summary
Advanced melanoma is one of the most intractable entities of medical oncology. curable through surgery at early stage, melanoma is noteworthy for its marked therapeutic resistance and proclivity for early metastasis. Mutational activation of the B-RAF serine/ threonine kinase or its upstream activator, the N-RAS small. 4] that can contribute to oncogenesis, the finding that N-RAS and B-RAF mutations are mutually exclusive in melanoma has prompted the notion that RAF mediates much of the transforming activity of RAS activation in this tumor type. Recent studies have shown that essentially all genes deregulated by RAF activation are through the MEK-ERK pathway [5], supporting MEK1/2 as the principal target of RAF activation. We identified key targets of RAS and RAF signaling [8,9,10] through differential gene expression and candidate gene approaches. We elected to take an unbiased genome-wide approach to identifying the relevant targets of RAS-RAF-MEK-ERK signaling in melanoma
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
