Journal
CANCER CELL
Volume 23, Issue 6, Pages 811-825Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2013.05.003
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Funding
- NIH [CA25874, CA047159, CA10815]
- Dr. Miriam and Scheldon G. Adelson Medical Research Foundation
- DFG [SFB1027, SFB 894 (A1), R3577/2-1, R3577/3-1]
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Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic nnultidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B(high) subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.
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