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

by Selleckchem | Aug 19 2023

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.

Comments:

The passage you provided describes the characteristics and treatment of NUT midline carcinoma (NMC), a rare and aggressive subtype of squamous carcinoma. NMC is driven by the BRD4-NUT fusion oncoprotein, which leads to the activation of oncogenic target genes. While BET-selective bromodomain inhibitors have shown some effectiveness in treating NMC, their efficacy is limited.

The passage suggests that combining selective inhibitors of the p300/CBP bromodomains (GNE-781 and OTX015) with BET bromodomain inhibitors can lead to synergistic effects in inhibiting NMC growth. The authors conducted experiments using a novel dual p300/CBP and BET bromodomain-selective inhibitor called NEO2734. They found that NEO2734 effectively inhibited NMC growth and induced cell differentiation in vitro. Furthermore, in xenograft models of disseminated NMC, NEO2734 demonstrated greater growth inhibition, tumor regression, and improved survival compared to a clinical BET inhibitor or standard chemotherapy.

Based on these findings, the authors propose that NEO2734 should be studied in clinical trials for NMC treatment. Additionally, the synergistic inhibition of NMC growth observed by inhibiting both CBP/p300 and BET bromodomains provides insights into the interplay between p300 and BRD4-NUT, shedding light on the underlying mechanisms driving this type of cancer.