Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma

Luigi Fattore, Ciro Francesco Ruggiero, Maria Elena Pisanu, Domenico Liguoro, Andrea Cerri, Susan Costantini, Francesca Capone, Mario Acunzo, Giulia Romano, Giovanni Nigita, Domenico Mallardo, Concetta Ragone, Maria Vincenza Carriero, Alfredo Budillon, Gerardo Botti, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto

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Abstract

Drug resistance imposes severe limitations to the efficacy of targeted therapy in BRAF-mutated metastatic melanoma. Although this issue has been mitigated by the development of combination therapies with BRAF plus MEK inhibitors, drug resistance inevitably occurs with time and results in clinical recurrences and untreatable disease. Hence, there is strong need of developing new combination therapies and non-invasive diagnostics for the early identification of drug-resistant patients. We report here that the development of drug resistance to BRAFi is dominated by a dynamic deregulation of a large population of miRNAs, leading to the alteration of cell intrinsic proliferation and survival pathways, as well as of proinflammatory and proangiogenic cues, where a prominent role is played by the miR-199b-5p/VEGF axis. Significant alterations of miRNA expression levels are detectable in tumor biopsies and plasma from patients after disease recurrence. Targeting these alterations blunts the development of drug resistance.

Original languageEnglish
Pages (from-to)1267-1282
Number of pages16
JournalCell Death and Differentiation
Volume26
Issue number7
DOIs
Publication statusPublished - Jul 2019

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Fattore, L., Ruggiero, C. F., Pisanu, M. E., Liguoro, D., Cerri, A., Costantini, S., Capone, F., Acunzo, M., Romano, G., Nigita, G., Mallardo, D., Ragone, C., Carriero, M. V., Budillon, A., Botti, G., Ascierto, P. A., Mancini, R., & Ciliberto, G. (2019). Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma. Cell Death and Differentiation, 26(7), 1267-1282. https://doi.org/10.1038/s41418-018-0205-5