2. Academic Validation
  3. Combined Targeting of the BRD4-NUT-p300 Axis in NUT Midline Carcinoma by Dual Selective Bromodomain Inhibitor, NEO2734

Combined Targeting of the BRD4-NUT-p300 Axis in NUT Midline Carcinoma by Dual Selective Bromodomain Inhibitor, NEO2734

  • Mol Cancer Ther. 2020 Jul;19(7):1406-1414. doi: 10.1158/1535-7163.MCT-20-0087.
Chevaun D Morrison-Smith 1,  Tatiana M Knox 1,  Ivona Filic 1,  Kara M Soroko 2,  Benjamin K Eschle 2,  Margaret K Wilkens 2,  Prafulla C Gokhale 2,  Francis Giles 3,  Andrew Griffin 4,  Bill Brown 5,  Geoffrey I Shapiro 6,  Beth E Zucconi 7,  Philip A Cole 7,  Madeleine E Lemieux 8,  Christopher A French 9
Affiliations

Affiliations

  • 1 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 2 Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 3 Developmental Therapeutics Consortium, Chicago, Ilinois.
  • 4 Praxis Precision Medicines, Cambridge, Massachusetts.
  • 5 Paraza Pharma Inc., Montreal, Quebec, Canada.
  • 6 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 7 Department of Medicine, Division of Genetics, Brigham and Women's Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
  • 8 Bioinfo, Plantagenet, Ontario, Canada.
  • 9 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. cfrench@bwh.harvard.edu.
PMID: 32371576 DOI: 10.1158/1535-7163.MCT-20-0087
Abstract

NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET-selective bromodomain inhibitors have demonstrated on-target activity in patients with NMC, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces cooperative depletion of MYC and synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain-selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells in vitro; findings that correspond with potentiated transcriptional effects from combined BET and p300 bromodomain inhibition. In three disseminated NMC xenograft models, NEO2734 provided greater growth inhibition, with tumor regression and significant survival benefit seen in two of three models, compared with a lead clinical BET inhibitor or "standard" chemotherapy. Our findings provide a strong rationale for clinical study of NEO2734 in patients with NMC. Moreover, the synergistic inhibition of NMC growth by CBP/p300 and BET bromodomain inhibition lays the groundwork for greater mechanistic understanding of the interplay between p300 and BRD4-NUT that drives this Cancer.

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