Elimination of Slow-Cycling Melanoma Cells Overcomes Drug Resistance

Cytotoxic chemotherapeutics and targeted therapies eliminate rapidly proliferating tumor cells but often enrich for slowly dividing cancer stem cells that confer drug resistance and facilitate tumor relapse. Recent studies have identified a slow-cycling subpopulation of melanoma cells characterized by high expression of lysine (K)-specific demethylase 5B (KDM5B, also known as JARID1B) that is required for tumor maintenance, suggesting that these cells may contribute to multidrug resistance in melanoma. In support of this idea, Roesch and colleagues found that treatment with various anticancer drugs, including cisplatin, bortezomib, and the BRAF inhibitor vemurafenib, enriched for JARID1B^high, intrinsically resistant melanoma cells in vitro as well as in mouse xenografts and primary melanoma samples. This therapy-induced increase in resistant cells was due to selection of a preexisting subpopulation of JARID1B^high cells, which gave rise to rapidly dividing cells with elevated repopulation potential. In contrast, depletion of JARID1B stimulated the proliferation of these slow-cycling cells and enhanced the sensitivity of melanoma xenografts to antitumor therapies. JARID1B^high melanoma cells exhibited upregulation of mitochondrial proteins involved in bioenergetic metabolism, in particular enzymes that regulate oxidative phosphorylation, such as NADH dehydrogenase and ATP synthase, resulting in increased oxygen consumption and hydrogen peroxide production. Pharmacologic blockade of the mitochondrial respiratory chain using inhibitors of ATP synthase or complex I diminished JARID1B expression and induced long-term growth suppression in vitro. Furthermore, combined treatment with low-dose mitochondrial respiratory chain inhibitors and anticancer drugs prevented accumulation of the JARID1B^high subpopulation and resulted in more potent suppression of tumor cell growth and invasion. These results suggest that targeted elimination of slow-cycling JARID1B^high melanoma cells may overcome multidrug resistance and improve therapeutic efficacy and duration in patients with melanoma.

Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM, Speicher D, et al. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B^high cells. Cancer Cell 2013;23:811–25.