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

Lisa Koetz-Ploch, Douglas Hanniford, Igor Dolgalev, Elena Sokolova, Judy Zhong, Marta Díaz-Martínez, Emily Bernstein, Farbod Darvishian, Keith T. Flaherty, Paul B. Chapman, Hussein Tawbi, Eva Hernando

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish
Pages (from-to)328-338
Number of pages11
JournalPigment Cell and Melanoma Research
Volume30
Issue number3
DOIs
StatePublished - May 2017

Keywords

  • BRAF inhibitor
  • apoptosis
  • melanoma
  • microRNA
  • resistance

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