1. miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators
- Author
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Elisabetta Ferrero, Marina Ferrarini, Chiara Gargiuli, Viviana Vallacchi, Michele Del Vecchio, Macarena Gomez Lira, Eriomina Shahaj, Mara Cossa, Elena Tamborini, Barbara Vergani, Luca Lalli, Mario Santinami, Barbara Valeri, Monica Rodolfo, Gianfrancesco Gallino, Simona Frigerio, Veronica Huber, Marialuisa Sensi, Licia Rivoltini, Elisabetta Vergani, Lorenza Di Guardo, Matteo Dugo, Ilaria Mattavelli, Biagio Eugenio Leone, Vergani, E, Dugo, M, Cossa, M, Frigerio, S, Di Guardo, L, Gallino, G, Mattavelli, I, Vergani, B, Lalli, L, Tamborini, E, Valeri, B, Gargiuli, C, Shahaj, E, Ferrarini, M, Ferrero, E, Gomez Lira, M, Huber, V, Vecchio, M, Sensi, M, Leone, B, Santinami, M, Rivoltini, L, Rodolfo, M, and Vallacchi, V
- Subjects
Proto-Oncogene Proteins B-raf ,BRAF/MEK inhibitors ,medicine.medical_treatment ,lcsh:Medicine ,Drug resistance ,Models, Biological ,Biochemistry ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,miR-146a-5p ,Cell Line, Tumor ,microRNA ,medicine ,Humans ,Epigenetics ,BRAF/MEK inhibitor ,lcsh:QH573-671 ,Extracellular Signal-Regulated MAP Kinases ,Melanoma ,Protein Kinase Inhibitors ,Molecular Biology ,030304 developmental biology ,Mitogen-Activated Protein Kinase Kinases ,0303 health sciences ,Kinase ,business.industry ,lcsh:Cytology ,Research ,lcsh:R ,NF-kappa B ,Cell Biology ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,MicroRNAs ,Cyclooxygenase 2 ,Drug Resistance, Neoplasm ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,Inflammation Mediators ,Melanoma resistance ,business ,Proto-Oncogene Proteins c-akt ,COX2 ,Signal Transduction - Abstract
Background Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance. Methods The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy. Results miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor. Conclusions Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. Graphical Abstract
- Published
- 2020
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