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