MITF Modulates Therapeutic Resistance through EGFR Signaling

J Invest Dermatol. 2015 Jul;135(7):1863-1872. doi: 10.1038/jid.2015.105. Epub 2015 Mar 19.

Abstract

Response to targeted therapies varies significantly despite shared oncogenic mutations. Nowhere is this more apparent than in BRAF (V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace. Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs), although the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR-induced vemurafenib resistance is ligand dependent. We employed whole-genome expression analysis and discovered that vemurafenib resistance correlated with the loss of microphthalmia-associated transcription factor (MITF), along with its melanocyte lineage program, and with the activation of EGFR signaling. An inverse relationship between MITF, vemurafenib resistance, and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients' tumor specimens. Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype. In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors. These findings indicate that an "autocrine drug resistance loop" is suppressed by melanocyte lineage signal(s), such as MITF. This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition.

Publication types

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

MeSH terms

  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / drug effects
  • ErbB Receptors / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Indoles / pharmacology*
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Microphthalmia-Associated Transcription Factor / drug effects*
  • Microphthalmia-Associated Transcription Factor / genetics*
  • Molecular Targeted Therapy / methods
  • Proto-Oncogene Proteins B-raf / drug effects
  • Proto-Oncogene Proteins B-raf / genetics
  • Sensitivity and Specificity
  • Signal Transduction
  • Skin Neoplasms
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured / drug effects
  • Vemurafenib

Substances

  • Indoles
  • Microphthalmia-Associated Transcription Factor
  • Sulfonamides
  • Vemurafenib
  • EGFR protein, human
  • ErbB Receptors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf

Supplementary concepts

  • Melanoma, Cutaneous Malignant