title: 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 BRAFV600Emelanoma 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.
authors.affiliation: Department of Pathology, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.|NYU Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Koetz-Ploch
authors.affiliation: Department of Pathology, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.|NYU Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanniford
authors.affiliation: Genomics Technology Center, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Dolgalev
authors.affiliation: Department of Pathology, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.|NYU Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Sokolova
authors.affiliation: NYU Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.|Division of Biostatistics, Department of Environmental Medicine, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Centro Investigaciones Biológicas, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Díaz-Martínez
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Bernstein
authors.affiliation: Department of Pathology, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.|NYU Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
authors.affiliation: Massachusetts General Hospital, Harvard University, Boston, MA, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hussein
authors.initials: H
authors.lastname: Tawbi
authors.affiliation: Department of Pathology, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.|NYU Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Eva
authors.identifier: 0000-0003-1023-0312
authors.initials: E
authors.lastname: Hernando
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; D050998:bcl-2 Homologous Antagonist-Killer Protein; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitor; apoptosis; melanoma; microRNA; resistance