Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

Nat Commun. 2014 Dec 15;5:5712. doi: 10.1038/ncomms6712.

Abstract

Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.

Publication types

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

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Imatinib Mesylate
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Microphthalmia-Associated Transcription Factor / genetics*
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Oximes / pharmacology
  • Piperazines / pharmacology
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Pyridones / pharmacology
  • Pyrimidines / pharmacology
  • Pyrimidinones / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Sulfonamides / pharmacology
  • Vemurafenib
  • Xenograft Model Antitumor Assays

Substances

  • Aminopyridines
  • Antineoplastic Agents
  • Benzamides
  • Imidazoles
  • Indoles
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
  • Oximes
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyridones
  • Pyrimidines
  • Pyrimidinones
  • Sulfonamides
  • Vemurafenib
  • trametinib
  • Imatinib Mesylate
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
  • dabrafenib