Micro<scp>RNA</scp>‐125a promotes resistance to <scp>BRAF</scp> inhibitors through suppression of the intrinsic apoptotic pathway

Abstract

Summary Melanoma patients with BRAF V 600E ‐ mutant tumors display striking responses to BRAF inhibitors ( BRAF i); however, almost all invariably relapse with drug‐resistant disease. Here, we report that micro RNA ‐125a ( miR‐125a ) expression is upregulated in human melanoma cells and patient tissues upon acquisition of BRAF i resistance. We show that miR‐125a induction confers resistance to BRAF V 600E melanoma cells to BRAF i by directly suppressing pro‐apoptotic components of the intrinsic apoptosis pathway, including BAK 1 and MLK 3. Apoptotic suppression and prolonged survival favor reactivation of the MAPK and AKT pathways by drug‐resistant melanoma cells. We demonstrate that miR‐125a inhibition suppresses the emergence of resistance to BRAF i and, in a subset of resistant melanoma cell lines, leads to partial drug resensitization. Finally, we show that miR‐125a upregulation is mediated by TGF β signaling. In conclusion, the identification of this novel role for miR‐125a in BRAF i resistance exposes clinically relevant mechanisms of melanoma cell survival that can be exploited therapeutically.