Towards a molecular profile of melanoma: Dysregulation of the Ras/Raf/ERK pathway

Abstract

7555 Background: Signal transduction pathways are increasingly being studied in melanoma. However, only the advent of chip technology and mass spectrometry has enabled the simultaneous analysis of multiple genes and gene products from melanoma samples. Methods: We attempted to analyze the Ras/Raf/ERK pathway in malignant melanoma specimens and metastases in comparison with normal human melanocytes and several melanoma cell lines. Results: By multidimensional scaling plot analysis melanoma metastases clustered in three different groups: two groups had similar expression profiles with the melanoma cell line BLM being representative of one cluster. Further confirmation on the protein level was obtained for the mitogen-activated protein kinase kinase (MEK)-1 and 3, that was highly upregulated as well as the downstream regulated mitogen-activated protein kinases (MAPK) p38 and extracellular-regulated kinase (ERK)1/2 (p44/42) in the majority of the analyzed samples. Importantly, phosphorylated ERK1/2 (p44/42 MAPK) as the functionally active signaling kinase, was abundant in most analyzed melanomas (4 of 6) as evidenced by Western blot analysis and immunohistochemistry (17 of 24 specimens), respectively. Conclusions: In summary, the Ras/Raf/ERK pathway that is relevant for proliferation, survival and angiogenesis seems to be critically involved in the development of melanoma without the pre-requirement of activating B-raf mutations. Ultimately, such molecular profiling may lead to a molecular classification of melanoma and may help to identify particular subgroups with regard to response to therapy, metastasis, and perhaps even prognosis. No significant financial relationships to disclose.