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.
Highlights
Very little is known about the changes affecting the entire miRNAome during the progressive development of drug resistance to MAPK inhibitors
BRAF mutational status in these two melanoma cell lines was confirmed by direct sequencing (Fig. 1b)
We found several autophagy-related genes such as AMBRA1, ATG5, ATG12, ATG13 and ATG4B (Fig. 3e), which could be potentially downregulated in BRAFi-resistant melanoma cells
Summary
These authors contributed : Luigi Fattore, Ciro Francesco Ruggiero, Rita Mancini, Gennaro Ciliberto. “Magna Graecia” of Catanzaro, Catanzaro, Italy 3 Department of Molecular and Clinical Medicine, University of. Roma “Sapienza”, Rome, Italy 4 IRCCS, National Cancer Institute of Naples “Fondazione G. Pascale”, Naples, Italy 5 Division of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA 6 Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
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