Epigenetic modulation reveals differentiation state specificity of oncogene addiction
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 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 09, 2021
- Source ID
- 10.1038/s41467-021-21784-2
Entities
People
- Elisabeth D. Martínez
- Mehwish Khaliq
- Mohammad Fallahi-Sichani
- Mohan Manikkam
Organizations
- Cancer Prevention and Research Institute of Texas
- Elsa U. Pardee Foundation
- National Institutes of Health
- Robert A. Welch Foundation
- United States Department of Defense
- United States Department of Health and Human Services
- V Foundation for Cancer Research