A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations

Cell. 2010 Apr 2;141(1):69-80. doi: 10.1016/j.cell.2010.02.027.

Abstract

Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly "drug-tolerant" cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Chromatin / metabolism
  • Chromatin / pathology
  • DNA Damage
  • Drug Resistance, Neoplasm*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Demethylases / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Receptor, IGF Type 1 / metabolism

Substances

  • Chromatin
  • Histone Deacetylase Inhibitors
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4A protein, human
  • Receptor, IGF Type 1