Combining inhibitors of Brd4 and cyclin-dependent kinase can decrease tumor growth in neuroblastoma with MYCN amplification.

Abstract

INTRODUCTION:

High-risk neuroblastoma is a deadly disease; poor prognosticators are MYCN-amplification and TERT-overexpression. We hypothesized that Gene Set Enrichment Analysis (GSEA) could identify pathways associated with MYCN-amplification and that inhibition of these pathways could decrease tumor growth.

METHODS:

We analyzed the Neuroblastoma-Kocak dataset (GSE45547, n = 649) and identified pathways associated with MYCN-amplification. Inhibitors were selected from upregulated gene sets for in vitro cytotoxicity testing using ST16-patient-derived primary neuroblastoma cells and in vivo testing using orthotopic ST16-patient-derived xenografts (PDX) in mice. Tumor volume was measured with ultrasound and tumor sections examined after H&E staining.

RESULTS:

GSEA identified significantly overexpressed gene sets in MYCN-amplified tumors including MYC targets, cell cycle mitotic genes, TERT associated genes, loss of RB1 gene sets, and E2Fs targets. Several genes were potential Bromodomain-containing protein 4 (Brd4) targets, making Brd4 inhibitors - JQ1, AZD5153 - and cyclin-dependent kinase (Brd4's binding partner) inhibitors - dinaciclib - potential therapeutic agents. JQ1 and dinaciclib were synergistic in inducing cytotoxicity in vitro. Dinaciclib-AZD5153 in vivo decreased tumor size compared to control, and increased tumor lymphocyte infiltration and necrosis on histology.

CONCLUSIONS:

GSEA is a powerful approach to identify upregulated genes and potential therapeutic targets. Dinaciclib-AZD5153 combination therapy can be effective against MYCN-amplified and TERT-overexpressing neuroblastoma tumors.

• Authors: Lauren Wood, Min Huang, Jasmine Zeki, Miao Gong, Jordan Taylor, Hiroyuki Shimada, Bill Chiu
• Journal: Journal of pediatric surgery (J Pediatr Surg) Vol. 56 Issue 7 Pg. 1199-1202 (Jul 2021) ISSN: 1531-5037 [Electronic] United States
• PMID: 33838899 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• BRD4 protein, human
• Cell Cycle Proteins
• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Nuclear Proteins
• Transcription Factors
• Cyclin-Dependent Kinases

Topics

• Animals
• Cell Cycle Proteins (genetics)
• Cell Line, Tumor
• Cyclin-Dependent Kinases
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• N-Myc Proto-Oncogene Protein (genetics, metabolism)
• Neuroblastoma (drug therapy, genetics)
• Nuclear Proteins (genetics, metabolism)
• Transcription Factors