Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-Cycling JARID1Bhigh Cells
Menée in vitro et in vivo, cette étude met en évidence l'intérêt d'une stratégie basée sur l'inhibition de l'enzyme OXPHOS pour surmonter une résistance aux inhibiteurs de BRAF dans le traitement d'un mélanome métastatique
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 JARID1Bhigh 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. "Slow-cycling melanoma cells expressing JARID1B show intrinsic multidrug resistance "Slow-cycling melanoma cells show upregulation of OXPHOS "Inhibition of OXPHOS sensitizes slow-cycling cells to therapy "OXPHOS inhibition can overcome drug resistance, irrespective of melanoma genotypes