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

Cell Death Differ. 2019 Jul;26(7):1267-1282. doi: 10.1038/s41418-018-0205-5. Epub 2018 Sep 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics*
  • Drug Screening Assays, Antitumor
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / genetics*
  • Melanoma / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Mutation*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Vemurafenib / pharmacology*


  • Antineoplastic Agents
  • MicroRNAs
  • Protein Kinase Inhibitors
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf