We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Micro RNA-125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway.
- Authors
Koetz ‐ Ploch, Lisa; Hanniford, Douglas; Dolgalev, Igor; Sokolova, Elena; Zhong, Judy; Díaz ‐ Martínez, Marta; Bernstein, Emily; Darvishian, Farbod; Flaherty, Keith T.; Chapman, Paul B.; Tawbi, Hussein; Hernando, Eva
- Abstract
Melanoma patients with BRAF V 600E -mutant tumors display striking responses to BRAF inhibitors ( BRAFi); however, almost all invariably relapse with drug-resistant disease. Here, we report that micro RNA-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 V 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 TGF β 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.
- Subjects
MELANOMA; MICRORNA; BRAF genes; APOPTOSIS; DRUG resistance in cancer cells; CANCER cells; PATIENTS
- Publication
Pigment Cell & Melanoma Research, 2017, Vol 30, Issue 3, p328
- ISSN
1755-1471
- Publication type
Article
- DOI
10.1111/pcmr.12578