期刊
PIGMENT CELL & MELANOMA RESEARCH
卷 30, 期 3, 页码 328-338出版社
WILEY
DOI: 10.1111/pcmr.12578
关键词
melanoma; BRAF inhibitor; resistance; microRNA; apoptosis
资金
- NIH-NCI [R01CA155234]
- Pershing Square Sohn Cancer Research Alliance
- Department of Defense [W81XWH-14-1-0230]
Melanoma patients with BRAF(V600E)-mutant tumors display striking responses to BRAF inhibitors (BRAFi); however, almost all invariably relapse with drug-resistant disease. Here, we report that microRNA-125a (miR-125a) expression is upregulated in human melanoma cells and patient tissues upon acquisition of BRAFi resistance. We show that miR-125a induction confers resistance to BRAF(V600E) melanoma cells to BRAFi by directly suppressing pro-apoptotic components of the intrinsic apoptosis pathway, including BAK1 and MLK3. 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 BRAFi 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 beta signaling. In conclusion, the identification of this novel role for miR-125a in BRAFi resistance exposes clinically relevant mechanisms of melanoma cell survival that can be exploited therapeutically.
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