2. Academic Validation
  3. GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer

GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer

  • Mol Cancer Res. 2019 Jul;17(7):1503-1518. doi: 10.1158/1541-7786.MCR-18-1121.
Samantha M Bevill 1,  Jose F Olivares-Quintero 1,  Noah Sciaky 1,  Brian T Golitz 1,  Darshan Singh 1,  Adriana S Beltran 1,  Naim U Rashid 2,  Timothy J Stuhlmiller 1,  Andrew Hale 3,  Nathaniel J Moorman 3,  Charlene M Santos 4,  Steven P Angus 1,  Jon S Zawistowski 1,  Gary L Johnson 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • 2 Department of Biostatistics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • 3 Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • 4 Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • 5 Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. glj@med.unc.edu.
PMID: 31000582 DOI: 10.1158/1541-7786.MCR-18-1121
Abstract

Screening of an inhibitor library targeting kinases and epigenetic regulators identified several molecules having antiproliferative synergy with extraterminal domain (BET) bromodomain (BD) inhibitors (JQ1, OTX015) in triple-negative breast Cancer (TNBC). GSK2801, an inhibitor of BAZ2A/B BDs, of the imitation switch chromatin remodeling complexes, and BRD9, of the SWI/SNF complex, demonstrated synergy independent of BRD4 control of P-TEFb-mediated pause-release of RNA polymerase II. GSK2801 or RNAi knockdown of BAZ2A/B with JQ1 selectively displaced BRD2 at promoters/enhancers of ETS-regulated genes. Additional displacement of BRD2 from rDNA in the nucleolus coincided with decreased 45S rRNA, revealing a function of BRD2 in regulating RNA polymerase I transcription. In 2D cultures, enhanced displacement of BRD2 from chromatin by combination drug treatment induced senescence. In spheroid cultures, combination treatment induced cleaved Caspase-3 and cleaved PARP characteristic of Apoptosis in tumor cells. Thus, GSK2801 blocks BRD2-driven transcription in combination with BET inhibitor and induces Apoptosis of TNBC. IMPLICATIONS: Synergistic inhibition of BDs encoded in BAZ2A/B, BRD9, and BET proteins induces Apoptosis of TNBC by a combinatorial suppression of ribosomal DNA transcription and ETS-regulated genes.

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