Epigenetic modulation reveals differentiation state specificity of oncogene addiction

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 screened 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 identified 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 remained insensitive, the anti-tumor efficacy of each inhibitor was 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.