Epigenetic modulation reveals differentiation state specificity of oncogene addiction

Nat Commun. 2021 Mar 9;12(1):1536. doi: 10.1038/s41467-021-21784-2.


Hyperactivation of the MAPK signaling pathway motivates the clinical use of MAPK inhibitors for BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency, diminishing the efficacy of MAPK inhibitors. To identify key regulators of such variability, we screen 276 epigenetic-modifying compounds, individually or combined with MAPK inhibitors, across genetically diverse and isogenic populations of melanoma cells. Following single-cell analysis and multivariate modeling, we identify three classes of epigenetic inhibitors that target distinct epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET bromodomain proteins. While melanocytes remain insensitive, the anti-tumor efficacy of each inhibitor is predicted based on melanoma cells' differentiation state and MAPK activity. Our systems pharmacology approach highlights a path toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.

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

  • Animals
  • Cell Differentiation / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Epigenesis, Genetic / drug effects
  • Epigenomics / methods*
  • Female
  • Histone Demethylases / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • MAP Kinase Signaling System / drug effects
  • Melanocytes / metabolism
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Mice
  • Mice, Nude
  • Mutation
  • Oncogene Addiction* / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / genetics
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays


  • Protein Kinase Inhibitors
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4B protein, human
  • KDM1A protein, human
  • Proto-Oncogene Proteins B-raf