Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition

Abstract

Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma.

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

“…Recent reports have shown that JQ1 suppresses growth of neuroblastoma in a set of in vivo models, including orthotopic transplantation of patient-derived xenografts and the TH-MYC mouse model (19,31). To determine the therapeutic effects of the TP-scaffold inhibitors in aggressive neuroblastoma, we established an s.c. xenograft model of MYCN-amplified neuroblastoma in immunocompromised mice using the SKNBE2 cell line.…”

“…The second BD, BD2, selects for acetylated nonhistone proteins, though it is also capable of associating with acetylated histones H3 and H4. In the past few years, a number of BRD4-specific inhibitors have been developed, with some showing therapeutic effects in cancer models for NUT midline carcinoma, multiple myeloma, lymphoid leukemia, myeloid leukemia, and neuroblastoma (7,8,10,12,(18)(19)(20)(21)(22)(23).Because MYC itself has been proven to be a difficult therapeutic target, the PI3K-AKT-mTOR pathway and inhibition of PI3K kinase activity in particular has been a main focus of drug development (4, 24). However, inhibition of PI3K to enhance degradation of MYC provides only a limited therapeutic effect and is often followed by the development of resistance to the drug (25).…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…The pathologic activation of MYCN plays a central role in high-risk neuroblastoma, while bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in in vivo neuroblastoma models. 67 Histone modifying enzymes: Role in brain cancer therapy…”

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

“…Recently, the bromodomain inhibitor, JQ1, was shown to target N-myc-amplified tumors by blocking N-myc-dependent transcription, impairing growth, and inducing apoptosis (86). Knockdown of the bromodomain protein BRD4 phenocopied these effects.…”