Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress

Cancer Cell. 2018 May 14;33(5):890-904.e5. doi: 10.1016/j.ccell.2018.03.017. Epub 2018 Apr 12.


Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase-mediated resistance to mitogen-activated protein kinase targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis. Therefore, ferroptosis-inducing drugs present an orthogonal therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies.

Keywords: combination therapy; differentiation; ferroptosis; immunotherapy; kinase inhibitor therapy; melanoma; pharmacogenomics; systems biology.

Publication types

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

MeSH terms

  • Cell Dedifferentiation
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Methylation
  • Drug Resistance, Neoplasm / drug effects
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Regulatory Networks
  • Humans
  • Iron / metabolism*
  • Iron / toxicity
  • Melanoma / classification*
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Oxidative Stress / drug effects
  • Piperazines
  • Signal Transduction
  • Vemurafenib / pharmacology*


  • Piperazines
  • erastin
  • Vemurafenib
  • Iron