Plasticity of Drug-Naïve and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program
Proposed model for the impact of targeted therapeutics, vemurafenib (PLX) and trametinib (TRA) on differentiated/pigmented phenotype of melanoma cells. (a) Drug-naïve melanoma cells show patient-related variability in MITF-M level and execution of differentiation/pigmentation program. This is reflected in the predominance of either dedifferentiated phenotype (high percentages of MIT cells, marked in green) or differentiated phenotype (high percentages of MIT cells, marked in red). Acute exposure to vemurafenib or trametinib could lead to increased expression of pigmentation-related genes in MITF- melanoma cell lines. Contrary to effects of acute treatment, acquired drug resistance developed by MITF- cells was not unidirectional and was accompanied either with enhanced level of MITF-M and expression of pigmentation-related genes or opposite, with dedifferentiation process. This dedifferentiation process can be either reversible or irreversible as demonstrated by changes induced by drug removal (“drug holiday”) followed by reexposure to drugs. In this study, MC1 variant was harboured exclusively by irreversibly dedifferentiated MITF- melanomas, either drug-naïve or resistant to vemurafenib (both marked in green). (b) Simplified schematic illustration of the signalling pathway contributing to expression of pigmentation-related genes in melanoma. Receptor MC1R on melanocytes is activated by α-MSH mainly synthesized by keratinocytes in response to UV light, but on melanoma cells autocrine activation of MC1R can occur. Activated MC1R increases cAMP level causing activation of CREB, which is one of transcription factors regulating MITF-M expression. MITF-M induces expression of pigmentation-related genes, MLANA, PMEL, TYR, and DCT, among others. Our results strongly suggest that this pathway is not active in drug-naïve cells carrying MC1 variant and drug-resistant melanoma cells that acquired a corresponding homozygous mutation. WT, nonmutated MC1R.
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