The majority of melanomas share a common mutation (V600E) in the B-RAF kinase. Melanocytes with B-RAFV600E mutation constitutively activate the mitogen-activated protein kinase pathway (MAPK). BRAF inhibitors are effective therapeutics in the clinic, but drug resistance always occurs either through reactivation of the MAPK pathway or through alternative signaling pathways. In B-RAF mutant melanoma cells, protein kinase c ε, θ, and η mediate resistance in the presence of PLX4720 through an unknown mechanism. We aimed to identify which signaling pathways or genes were the source of PKC-mediated resistance. Analysis of 24 candidate melanoma-relevant signaling pathways via Western Blotting did not identify the cellular pathways responsible for PKC-mediated resistance. However, Luminex phospho-tyrosine kinase profiling assay indicated a large amount of ERBB2 phosphorylation in all protein kinase c’s both in the absence and the presence of the drug. Interestingly, ERBB2 phosphorylation was seen in previous experiments. Understanding the signaling pathways of PRKC ε, η, and θ will allow for effective long-term treatment to be made for melanoma patients who have become resistant to the therapeutic drug.
*Funded by the National Cancer Institute's Integrative
Cancer Biology Program (ICBP)
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