In the initial therapeutic response phase, an immediate activation of the PAX3-MITF-PGC1α axis protects a subset of melanoma cells from MAPKi-induced cell death via MITF-mediated survival signaling, resulting in an early drug-tolerant state characterized by an enrichment of MITFhigh hyperdifferentiated populations (16, 185–187). The gene discussed is MITF; the disease is melanoma.