BET inhibitors: a novel epigenetic approach

Ann Oncol. 2017 Aug 1;28(8):1776-1787. doi: 10.1093/annonc/mdx157.


Epigenetics has been defined as 'the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.' Currently, several classes of anticancer drugs function at the epigenetic level, including inhibitors of DNA methyltransferase, histone deacetylase (HDAC), lysine-specific demethylase 1, zeste homolog 2, and bromodomain and extra-terminal motif (BET) proteins.BET proteins have multiple functions, including the initiation and elongation of transcription and cell cycle regulation. In recent years, inhibitors of BET proteins have been developed as anticancer agents. These inhibitors exhibit selectivity for tumor cells by preferentially binding to superenhancers, noncoding regions of DNA critical for the transcription of genes that determine a cell's identity. Preclinical research on BET inhibitors has identified them as a potential means of targeting MYC.Early clinical trials with BET inhibitors have had mixed results, with few responses in both hematologic and solid tumors that tend to be short-lived. Toxicities have included severe, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea; GI side-effects, fatigue, and low-grade dysgeusia have limited compliance. However, preclinical data suggest that BET inhibitors may have a promising future in combination with other agents. They appear to be able to overcome resistance to targeted agents and have strong synergy with immune checkpoint inhibitors as well as with multiple epigenetic agents, particularly HDAC inhibitors. In many instances, BET and HDAC inhibitors were synergistic at reduced doses, suggesting a potential means of avoiding the overlapping toxicities of the two drug classes.BET inhibitors provide a novel approach to epigenetic anticancer therapy. However, to date they appear to have limited efficacy as single agents. A focus on BET inhibitors in combination with other drugs such as targeted and/or as other epigenetic agents is warranted, due to limited monotherapy activity, including pharmacodynamic correlatives differential activity amongst select drug combinations.

Keywords: BET inhibitors; BET proteins; epigenetic anticancer therapy.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors
  • Drug Synergism
  • Epigenesis, Genetic*
  • Genes, myc
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Proteins / antagonists & inhibitors*


  • Antineoplastic Agents
  • B7-H1 Antigen
  • CD274 protein, human
  • Proteins
  • bromodomain and extra-terminal domain protein, human