Targeting basal-like breast tumors with bromodomain and extraterminal domain (BET) and polo-like kinase inhibitors

Oncotarget. 2017 Mar 21;8(12):19478-19490. doi: 10.18632/oncotarget.14465.

Abstract

Metastatic triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options, and no targeted therapies available. Triple negative tumors and the basal-like genomic subtype, are both characterized by a high proliferation rate and an increase in cell division. In this context, protein kinases involved in the mitotic formation have a relevant role in this tumor subtype. Recently, Bromodomain and extraterminal domain (BET) inhibitors have shown to be active in this disease by modulating the expression of several transcription factors. In this article, by using an "in silico" approach, we identified genomic functions that can be inhibited pharmacologically in basal-like tumors. Functional annotation analyses identified "cell division" and "regulation of transcription" as upregulated functions. When focus on cell division, we identified the polo-like kinase 1 (PLK) as an upregulated kinase. The PLK inhibitor Volasertib had the strongest anti-proliferative effect compared with other inhibitors against mitotic kinases. Gene expression analyses demonstrated that the BET inhibitor JQ1 reduced the expression of kinases involved in cell division, and synergized with Volasertib in a panel of triple negative cell lines. Combination of both agents augmented cell death. Similarly, combination of both compounds reduced the expression of stem cell markers. Globally, this data demonstrates the synergistic interaction between BET and PLK inhibitors, paving the way for their future clinical development.

Keywords: BET inhibitors; JQ1; breast cancer; polo-like kinases; triple negative breast cancer.

MeSH terms

  • Apoptosis / drug effects
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Basal Cell / drug therapy*
  • Carcinoma, Basal Cell / metabolism
  • Carcinoma, Basal Cell / pathology
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Proliferation / drug effects
  • Female
  • Histone Chaperones
  • Humans
  • Neoplasm Invasiveness
  • Nuclear Proteins / antagonists & inhibitors*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Tumor Cells, Cultured

Substances

  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Histone Chaperones
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • BRD1 protein, human
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1