Melanoma cells can develop BRAF inhibitor resistance by acquiring de novo mutations or by activation of cell signalling in the absence of genetic mutation. Recent findings demonstrate that exogenous growth factors can rescue cells from drug inhibition suggesting the extracellular environment can mediate resistance. Melanoma cells release exosomes into the extracellular environment. Exosomes are complex vehicles that deliver functional protein and genetic material to recipient cells in a concentrated form that far exceeds what can be delivered through soluble factors alone. We hypothesised that exosomes released from drug resistant melanoma cells traffic to neighbouring and distant drug sensitive melanoma cells, transferring these functional characteristics. Exosomes were isolated from the media of melanoma cell lines and characterised by protein and miRNA composition, density and morphology. Exosomes isolated from BRAF inhibitor sensitive or resistant cells were incubated with recipient cells in the presence/absence of inhibitor then functional studies including motility, migration, invasion and proliferation assays performed.
Melanoma derived exosomes were found to mediate a phenotypic switch in recipient cells, thereby contributing to drug resistance. Specifically, exosomes isolated from BRAF inhibitor resistant cells transferred resistance to sensitive cells. Preliminary studies demonstrate differences in the proteomic and miRNA composition of exosomes derived from resistance cells. If cancer therapies are to become more effective, the study of treatment failure & its mechanisms are a priority. We have identified a mechanism which appears to mediate the transfer of functional characteristics including drug resistance between heterogeneous cell populations.