Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma

EMBO Mol Med. 2018 May;10(5):e8446. doi: 10.15252/emmm.201708446.


Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS-mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.

Keywords: BET; combination therapy; drug resistance; melanoma; mutant NRAS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / pharmacology
  • Animals
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Gene Expression Profiling / methods
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Proteomics / methods
  • Salvage Therapy / methods
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Xenograft Model Antitumor Assays*


  • Acetanilides
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Heterocyclic Compounds, 3-Ring
  • Nuclear Proteins
  • OTX015
  • Protein Kinase Inhibitors
  • Proteins
  • Transcription Factors
  • bromodomain and extra-terminal domain protein, human
  • MAP Kinase Kinase 1