Targeting the cancer epigenome: synergistic therapy with bromodomain inhibitors

Drug Discov Today. 2018 Jan;23(1):76-89. doi: 10.1016/j.drudis.2017.09.011. Epub 2017 Sep 22.

Abstract

Epigenetic and genomic alterations regulate the transcriptional landscape of cells during cancer onset and progression. Recent clinical studies targeting the epigenetic 'readers' (bromodomains) for cancer therapy have established the effectiveness of bromodomain (BRD) and extraterminal (BET) inhibitors in treating several types of cancer. In this review, we discuss key mechanisms of BET inhibition and synergistic combinations of BET inhibitors with histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), DNA methyltransferase inhibitors (DNMTi), kinase, B-cell lymphoma 2 (Bcl-2) and proteosome inhibitors, and immunomodulatory drugs for cancer therapy. We also highlight the potential of such combinations to overcome drug resistance, and the evolving approaches to developing novel BET inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Cycle Proteins
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Epigenesis, Genetic
  • Epigenomics
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism

Substances

  • Antineoplastic Agents
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Proteins
  • Transcription Factors
  • bromodomain and extra-terminal domain protein, human