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Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition

Anton Henssen1, Kristina Althoff2, Andrea Odersky3

  • 1Molecular Pharmacology & Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany. henssena@mskcc.org.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|December 4, 2015
PubMed
Abstract

Insights

The BET inhibitor OTX015 shows efficacy in neuroblastoma models by disrupting BRD4 binding to super-enhancers and MYCN target genes. This targeted approach offers a new therapeutic strategy for MYCN-driven neuroblastoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • BET protein inhibition demonstrates antitumoral effects in MYCN-amplified neuroblastoma.
  • BRD4 plays a crucial role in MYCN-driven neuroblastoma pathogenesis.

Purpose of the Study:

  • To evaluate the therapeutic efficacy of the BET inhibitor OTX015 in preclinical neuroblastoma models.
  • To further elucidate the role of BRD4 in MYCN-driven neuroblastoma.

Main Methods:

  • In vitro and in vivo assessment of OTX015 efficacy in human and murine MYCN-driven neuroblastoma models.
  • Ectopic MYCN expression to study BET inhibition effects under high MYCN conditions.
  • Chromatin immunoprecipitation coupled with DNA sequencing (ChIP-Seq) to analyze BRD4 binding and transcriptional effects.

Main Results:

  • OTX015 demonstrated therapeutic efficacy in preclinical MYCN-driven neuroblastoma models.
  • While MYCN repression was observed, ectopic MYCN expression did not abolish OTX015 effects, suggesting additional targets.
  • OTX015 disrupted MYCN target gene transcription by inhibiting BRD4 binding to super-enhancers and MYCN target genes.

Conclusions:

  • OTX015 is effective against both human and murine MYCN-driven neuroblastoma models.
  • BRD4 targets not only MYCN but also enhancers of MYCN target genes and super-enhancers.
  • These findings highlight OTX015 as a promising therapeutic agent for neuroblastoma.

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