Cancer Cell 23, 811–825 (2013)

Therapeutics that target activated mutants of the kinase RAF, such as vemurafenib, are initially effective in malignant melanoma, but tumors rapidly acquire resistance to the drug. A slow-replicating subpopulation of melanoma cells, marked by the expression of the histone 3 lysine 4 demethylase JARID1B, has been previously discovered. Roesch et al. now report that this subpopulation drives vemurafinib resistance by increasing cellular reliance on mitochondrial oxidative phosphorylation for energy production. In culture, exposure to vemurafenib increased the proportion of these slow-cycling cells in the dish. Similar results were achieved with different drugs, including cisplatin and bortezomib, indicating that this JARID1B-expressing subpopulation may contribute to resistance to multiple drugs. Quantitative proteomic profiling comparing JARID1B-expressing with nonexpressing cells revealed enriched expression of mitochondrial proteins involved in energy metabolism in the presence of JARID1B. Small molecule–mediated inhibition of respiratory chain enzymes decreased ATP production and increased cell death of JARID1B-expressing cells in culture and in three-dimensional colony-forming assays. Combinatorial treatment with vemurafinib and inhibitors of oxidative phosphorylation prevented the expansion of the JARID1B subpopulation and enhanced tumor cell death in culture and in xenograft tumor models. Taken together, these data suggest that oxidative phosphorylation drives the expansion of a drug-resistant subpopulation of tumor cells in melanoma and suggests that compounds that target this energy production system could help to eliminate this cell population.