Micro RNA ‐125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway

• Published in: Pigment cell and melanoma research Vol. 30; no. 3; pp. 328 - 338
• Main 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
• Format: Journal Article
• Language: English
• Published: 01-05-2017
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12578

Melanoma patients with
BRAF
V
600E
‐
mutant tumors display striking responses to
BRAF
inhibitors (
BRAF
i); 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
BRAF
i resistance. We show that
miR‐125a
induction confers resistance to
BRAF
V
600E
melanoma cells to
BRAF
i by directly suppressing pro‐apoptotic components of the intrinsic apoptosis pathway, including
BAK
1 and
MLK
3. 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
BRAF
i 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
BRAF
i resistance exposes clinically relevant mechanisms of melanoma cell survival that can be exploited therapeutically.