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

Cancer Cell. 2013 Jun 10;23(6):811-25. doi: 10.1016/j.ccr.2013.05.003.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm*
  • Electron Transport / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Indoles / pharmacology
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oligomycins / pharmacology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Sulfonamides / pharmacology
  • Vemurafenib

Substances

  • Antineoplastic Agents
  • Indoles
  • Nuclear Proteins
  • Oligomycins
  • Repressor Proteins
  • Sulfonamides
  • Vemurafenib
  • Jumonji Domain-Containing Histone Demethylases
  • KDM5B protein, human
  • Cisplatin