Dataset Information

Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.

ABSTRACT: The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4-NUT fusion oncoprotein. BRD4-NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types and is currently in clinical development. Antitumor activity was evaluated in four patients with advanced-stage NMC with confirmed BRD4-NUT fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate-use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of-concept evidence of clinical activity of a BRD inhibitor in targeting BRD4-NUT.We present the first clinical proof-of-concept that targeting BRD4-NUT with a BET inhibitor results in impressive and rapid antitumor activity in NMC. It offers strong potential for future clinical application in this rare patient population as either a single agent or in combination with other agents. Cancer Discov; 6(5); 492-500. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.

SUBMITTER: Stathis A

PROVIDER: S-EPMC4854801 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.

Stathis Anastasios A Zucca Emanuele E Bekradda Mohamed M Gomez-Roca Carlos C Delord Jean-Pierre JP de La Motte Rouge Thibault T Uro-Coste Emmanuelle E de Braud Filippo F Pelosi Giuseppe G French Christopher A CA

Cancer discovery 20160314 5

<h4>Unlabelled</h4>The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4-NUT fusion oncoprotein. BRD4-NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tu ...[more]

PMID: 26976114

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Project description:Aberrant changes in microRNAs (miRNAs) contribute to lymphomagenesis and represent potential therapeutic targets. OTX015 (MK-8628), a bromodomain and extra-terminal domain (BET) inhibitor (BETi), has demonstrated preclinical and clinical activity in haematological tumours. To better understand the mechanism of action of OTX015 we studied its effects on miRNAs in lymphomas. We performed miRNA profiling of DLBCL cells treated with OTX015 and observed changes in the expression levels of a subset of miRNAs, including miR-92a-1-5p, miR-21-3p, miR-155-5p and miR-96-5p, which are known to play a role in lymphomagenesis and/or resistance to chemotherapy. Analysis of publicly available BRD4 ChIP-Seq data of DLBCL cells treated with the BETi JQ1 showed that BRD4 was bound to the upstream regulatory regions of multiple miRNA genes and that this binding decreased following BETi. Alignment of our miRNA profiling data with the BRD4 ChIP-Seq data revealed that many miRNAs downregulated by OTX015 also exhibited reduced BRD4 binding in their promoter regions following BETi treatment, indicating that BRD4 directly modulated miRNA expression in lymphoma. Among the miRNAs upregulated in response to OTX015 was miR-96-5p, a miRNA known to play a role in B-cell transformation. In lymphomas, miR-96-5p transcription is repressed by the arginine methyltransferase PRMT5. In turn, PRMT5 translation is inhibited by miR-96-5p. We demonstrated that BRD4 bound to the 5’ regulatory region of PRMT5 and that following BET inhibition PRMT5 expression decreased, BRD4 binding to the 5’ region of PRMT5 was reduced and enrichment of PRMT5 at the miR-96-5p promoter lessened. Our results demonstrate that BRD4 binds to the promoters of miRNA genes to directly modulate their expression in lymphoma cells and that BETi administration results in decreased binding of BRD4 to the promoters of specific miRNAs to reduce their expression. Additionally, we show that BETi treatment can affect the expression of genes that control miRNA transcription to indirectly modulate miRNA expression. The data presented here indicate that the ability of BETi to inhibit or activate specific signalling pathways and processes critical to lymphoma cell proliferation and survival is in part due to changes in miRNA expression.

Dataset Information

Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.

Publications

Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.

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