Abstract
Abstract Background: NUT midline carcinoma (NMC) is an aggressive subtype of poorly differentiated squamous cell carcinoma, occurring anywhere along the trunk or the head, most commonly along the midline. NMC is characterized by chromosomal translocation resulting in the fusion of the gene nuclear protein in testis (NUT) and bromodomain and extraterminal domain (BET) proteins (BRD2,3,4 and BRDT). The acquired bromodomain region tethers the BRD-NUT fusion protein to acetylated chromatin. The molecular mechanism by which BRD-NUT is involved in the generation of NMC is unclear, although it seems to be related to massive disruption of normal gene regulation at key cell type–specific genes. After binding to acetylated chromatin through bromodomains, the NUT moiety of the fusion protein strongly interacts with and recruits E1A interacting protein of 300 kDa (EP300/P300), initiating cycles of BRD-NUT/P300 recruitment and creating chromatin “megadomains” enriched in histone H3 lysine 27 acetylation (H3K27ac), a specific enhancer and super-enhancer histone mark. The creation of these domains activates transcription of adjacent genes that seem to be critical for the progression of NMC. As BET inhibitors have shown activity in NMC and P300 is important in its pathophysiology, we examined the pre-clinical activity of NEO2734 and NEO1132, novel dual BET and P300/CBP inhibitors (Giles et al Abs #2510 ESMO 2018), in NMC. Results:Considering the important roles of BET proteins and P300 in NMC, two NMC-cell lines (1015 and 14169, C. French: Brigham and Women’s Hospital) were treated with dual BET and P300/CBP inhibitors NEO2734 and NEO1131 (Epigene Therapeutics Inc), BET inhibitors JQ1 and iBET155 (GSK525762) (Sigma-Aldrich) and P300/CBP inhibitor CPI-637 (MedChem Express) for comparison. The average IC50 values of the two molecules were 44.04 nM and 130.73 nM respectively in 1015 cell line and 77.37 nM and 123.95 nM in 14169 cell line. For the two cell lines, the dual inhibitor NEO2734 was more potent than NEO1131, IBET155 and p300 inhibitors. The 14169 cell line, with a higher number of genetic lesions than the 1015 cell line, was more resistant to NEO2734 than the 1015 cell line. Conclusions: The dual inhibitor NEO2734 showed superior in vitroanti-proliferative activity in two NMC cell lines compared with single BET and p300 inhibitors. We also observed the presence of two different cell populations (adherent and suspension cells) in both NMC cell lines with adherent cells being more resistant to NEO2734, Differences in the responses to NEO2734 in NMC are being studied to molecularly identify biomarkers of resistance. These data support the inclusion of patients with NMC in clinical studies of NEO2734. Citation Format: Tian Tian, Marc Cosín, Francis Giles, Irene Braña, Elena Garralda, Sandra Peiró. NEO2734, a novel dual BET and P300/CBP bromodomain inhibitor, is more active in NUT midline carcinoma than single agent BET or P300/CBP inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B008. doi:10.1158/1535-7163.TARG-19-B008
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