SOX10-mediated regulation of the MiR-106a/363 cluster drives RAF inhibitor resistance in BRAF-mutant melanoma.

Adaptive resistance to MAPK inhibitors remains a major clinical obstacle in BRAF-mutant melanoma, driven by reversible transcriptional and epigenetic reprogramming. Previous studies have implicated loss of SRY-box transcription factor 10 (SOX10) and concurrent activation of TGF-β signaling in this process, but the molecular link between them has remained unresolved. Here, we identify a SOX10-miR-106a/363-TGFBR2 regulatory axis that governs adaptive resistance. SOX10 directly activates transcription of the miR-106a/363 cluster through a distal cis-regulatory element. In turn, the miR-106a/363 cluster members miR-106a-5p and miR-20b-5p suppress TGFBR2 post-transcriptionally, while miR-363-3p indirectly reduces TGFBR2 expression by targeting SOX4, a transcriptional activator of TGFBR2. This dual-layered repression restrains TGF-β signaling and maintains drug sensitivity. Loss of SOX10 diminishes miR-106a/363 expression, derepresses TGFBR2, and promotes a mesenchymal-like, drug-tolerant state. Restoring miR-106a/363 expression partially re-sensitizes melanomas to RAF inhibitors in vivo. These findings reveal a previously unrecognized regulatory circuit linking SOX10 to TGF-β signaling and highlight the miR-106a/363 cluster as a potential therapeutic target to overcome adaptive resistance in melanoma.