Overcoming Intrinsic Multidrug Resistance in Melanoma by Blocking the Mitochondrial Respiratory Chain of Slow-cycling JARID1B(high) Cells

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2013 Jun 15

PMID 23764003

Citations 391

Authors

Alexander Roesch

Adina Vultur

Ivan Bogeski

Huan Wang

Katharina M Zimmermann

David Speicher

Christina Korbel

Matthias W Laschke

Phyllis A Gimotty

Stephan E Philipp

Elmar Krause

Sylvie Patzold

Jessie Villanueva

Clemens Krepler

Mizuho Fukunaga-Kalabis

Markus Hoth

Boris C Bastian

Thomas Vogt

Meenhard Herlyn

Affiliations

Soon will be listed here.

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.

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