Regulation of melanoma cellular plasticity by the Mediator complex drives therapeutic resistance

Melanoma exhibits profound cellular plasticity that enables adaptive responses to therapeutic pressure and ultimately drives treatment resistance. However, the transcriptional mechanisms governing melanoma cell-state transitions remain incompletely understood. Here, we identify the Mediator complex as a central regulator of melanoma cellular plasticity that promotes resistance to targeted therapy. Using genetic and pharmacological perturbations, we show that disruption of Mediator function induces melanoma cell-state switching, promotes dedifferentiation programs, characterized by loss of lineage-specific transcriptional programs and activation of survival-associated gene expression, and enhances resistance to MAPK pathway inhibition. Mechanistically, Mediator tail depletion rewires transcriptional networks governing cell identity and adaptive signaling, enabling melanoma cells to bypass MAPK pathway blockade. Collectively, our findings identify the Mediator tail module as a key transcriptional safeguard against melanoma dedifferentiation and reveal its unexpected role in suppressing cellular plasticity–driven resistance to targeted therapy.