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_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. Authors * Amy Donner View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions
ABOUT THIS ARTICLE CITE THIS ARTICLE Donner, A. Starving for ATP. _Nat Chem Biol_ 9, 468 (2013). https://doi.org/10.1038/nchembio.1303 Download citation * Published: 18 July 2013 * Issue
Date: August 2013 * DOI: https://doi.org/10.1038/nchembio.1303 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a
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