Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3

J Clin Invest. 2013 May;123(5):2155-68. doi: 10.1172/JCI65780. Epub 2013 Apr 1.


The mechanisms underlying adaptive resistance of melanoma to targeted therapies remain unclear. By combining ChIP sequencing with microarray-based gene profiling, we determined that ERBB3 is upregulated by FOXD3, a transcription factor that promotes resistance to RAF inhibitors in melanoma. Enhanced ERBB3 signaling promoted resistance to RAF pathway inhibitors in cultured melanoma cell lines and in mouse xenograft models. ERBB3 signaling was dependent on ERBB2; targeting ERBB2 with lapatinib in combination with the RAF inhibitor PLX4720 reduced tumor burden and extended latency of tumor regrowth in vivo versus PLX4720 alone. These results suggest that enhanced ERBB3 signaling may serve as a mechanism of adaptive resistance to RAF and MEK inhibitors in melanoma and that cotargeting this pathway may enhance the clinical efficacy and extend the therapeutic duration of RAF inhibitors.

Publication types

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

MeSH terms

  • Cell Survival
  • Enzyme Inhibitors / pharmacology
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Indoles / pharmacology
  • Lapatinib
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Melanoma / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Quinazolines / pharmacology
  • Receptor, ErbB-3 / metabolism*
  • Signal Transduction
  • Skin Neoplasms / metabolism*
  • Sulfonamides / pharmacology
  • Transcription, Genetic
  • raf Kinases / antagonists & inhibitors*
  • raf Kinases / metabolism


  • Enzyme Inhibitors
  • FOXD3 protein, human
  • Forkhead Transcription Factors
  • Indoles
  • PLX 4720
  • Quinazolines
  • Sulfonamides
  • Lapatinib
  • ERBB3 protein, human
  • Receptor, ErbB-3
  • raf Kinases
  • MAP Kinase Kinase Kinases