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


ABSTRACT: Melanoma patients with BRAFV600E -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 BRAFV600E 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? 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.

SUBMITTER: Koetz-Ploch L 

PROVIDER: S-EPMC5411293 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Koetz-Ploch Lisa L   Hanniford Douglas D   Dolgalev Igor I   Sokolova Elena E   Zhong Judy J   Díaz-Martínez Marta M   Bernstein Emily E   Darvishian Farbod F   Flaherty Keith T KT   Chapman Paul B PB   Tawbi Hussein H   Hernando Eva E  

Pigment cell & melanoma research 20170419 3


Melanoma patients with BRAF<sup>V</sup><sup>600E</sup> -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<sup>V</sup><sup>600E</sup> melanoma cells to BRAFi by directly suppressing pro-apoptotic compo  ...[more]

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