MicroRNA‐125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway |
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| Authors: | 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 |
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| Affiliation: | 1. Department of Pathology, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA;2. NYU Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA;3. Genomics Technology Center, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA;4. Division of Biostatistics, Department of Environmental Medicine, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA;5. Centro Investigaciones Biológicas, Madrid, Spain;6. Icahn School of Medicine at Mount Sinai, New York, NY, USA;7. Massachusetts General Hospital, Harvard University, Boston, MA, USA;8. Memorial Sloan‐Kettering Cancer Center, New York, NY, USA;9. MD Anderson Cancer Center, Houston, TX, USA |
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| 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 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. |
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| Keywords: | melanoma BRAF inhibitor resistance microRNA apoptosis |
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