title: Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells.
abstract: 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.
authors.affiliation: Department of Dermatology, The Saarland University Hospital, D-66421 Homburg/Saar, Germany. alexander.roesch@uks.eu
authors.forename: Alexander
authors.initials: A
authors.lastname: Roesch
authors.forename: Adina
authors.initials: A
authors.lastname: Vultur
authors.forename: Ivan
authors.initials: I
authors.lastname: Bogeski
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Zimmermann
authors.forename: David
authors.initials: D
authors.lastname: Speicher
authors.forename: Christina
authors.initials: C
authors.lastname: Körbel
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Laschke
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Philipp
authors.forename: Elmar
authors.initials: E
authors.lastname: Krause
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pätzold
authors.forename: Jessie
authors.initials: J
authors.lastname: Villanueva
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.forename: Mizuho
authors.initials: M
authors.lastname: Fukunaga-Kalabis
authors.forename: Markus
authors.initials: M
authors.lastname: Hoth
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004579:Electron Transport / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009687:Nuclear Proteins; D009840:Oligomycins; D012097:Repressor Proteins; D013449:Sulfonamides; D000077484:Vemurafenib; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human; D002945:Cisplatin