MicroRNA-125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway Journal Article


Authors: Koetz-Ploch, L.; Hanniford, D.; Dolgalev, I.; Sokolova, E.; Zhong, J.; Díaz-Martínez, M.; Bernstein, E.; Darvishian, F.; Flaherty, K. T.; Chapman, P. B.; Tawbi, H.; Hernando, E.
Article Title: MicroRNA-125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway
Abstract: Melanoma patients with BRAFV 600E-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 BRAFV 600E 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 TGFβ 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. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Keywords: melanoma; apoptosis; microrna; resistance; braf inhibitor
Journal Title: Pigment Cell & Melanoma Research
Volume: 30
Issue: 3
ISSN: 1755-1471
Publisher: Wiley Blackwell  
Date Published: 2017-05-01
Start Page: 328
End Page: 338
Language: English
DOI: 10.1111/pcmr.12578
PROVIDER: scopus
PMCID: PMC5411293
PUBMED: 28140520
DOI/URL:
Notes: Article -- Export Date: 2 June 2017 -- Source: Scopus
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  1. Paul Chapman
    326 Chapman