Epigenetic therapy in non-small-cell lung cancer: targeting DNA methyltransferases and histone deacetylases

Expert Opin Biol Ther. 2013 Sep;13(9):1273-85. doi: 10.1517/14712598.2013.819337. Epub 2013 Jul 17.


Introduction: Epigenetics refers to heritable modifications of DNA and associated chromatin components that influence gene expression without altering DNA coding sequence. Epigenetic dysregulation is a central contributor to oncogenesis and is increasingly a focus of interest in cancer therapeutic research. Two key levels of aberrant epigenetic control are DNA methylation and histone acetylation. Primary regulators of these epigenetic changes include DNA methyltransferases (DNMTs) and histone deacetylases (HDACs).

Areas covered: This review focuses on epigenetic changes in non-small-cell lung cancer and recent preclinical and clinical studies targeting these changes. DNMT inhibitors were previously explored at or near maximally tolerated doses, levels at which these agents are cytotoxic but have suboptimal effects on DNA methylation. Use of these inhibitors at substantially lower doses, in combination with HDAC inhibitors, can promote re-expression of silenced tumor suppressor genes, can result in major clinical responses and may alter tumor responsiveness to subsequent cytotoxic therapies.

Expert opinion: Combinatorial epigenetic therapy has demonstrated encouraging clinical activity, but many relevant questions remain. Global strategies influencing the epigenome may have both positive and potential negative long-term effects on cancer progression. Further clinical investigation of this approach, including exploratory studies to define predictive biomarkers, is warranted.

Publication types

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

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • DNA Modification Methylases / antagonists & inhibitors*
  • Drug Resistance, Neoplasm
  • Epigenesis, Genetic*
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology


  • Histone Deacetylase Inhibitors
  • DNA Modification Methylases