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bioRxiv · 10.1101/2020.05.04.077602

Epigenetic modulation extends the oncogene addiction paradigm on the basis of tumor cell differentiation state

Khaliq, M.·Manikkam, M.·Martinez, E. D.·Fallahi-Sichani, M.
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Abstract

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.

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Khaliq, M., Manikkam, M., Martinez, E. D., Fallahi-Sichani, M.. 2020-05-05. Epigenetic modulation extends the oncogene addiction paradigm on the basis of tumor cell differentiation state. https://doi.org/10.1101/2020.05.04.077602

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