Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1B^high Cells

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• 作者：Alexander Roesch¹ ; ² ; ^{alexander.roesch@uks.eu} ; Adina Vultur² ; Ivan Bogeski³ ; Huan Wang² ; Katharina M. Zimmermann¹ ; ³ ; David Speicher² ; Christina Kö ; rbel⁴ ; Matthias W. Laschke⁴ ; Phyllis A. Gimotty⁷ ; Stephan E. Philipp⁵ ; Elmar Krause⁶ ; Sylvie Pä ; tzold⁸ ; Jessie Villanueva² ; Clemens Krepler² ; Mizuho Fukunaga-Kalabis² ; Markus Hoth³ ; Boris C. Bastian⁹ ; Thomas Vogt¹ ; Meenhard Herlyn² ; ^{herlynm@wistar.org}
• 刊名：Cancer Cell
• 出版年：2013
• 出版时间：10 June, 2013
• 年：2013
• 卷：23
• 期：6
• 页码：811-825
• 全文大小：4350 K

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Summary

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 multidrug 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.