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Neoplasia. 2018 Oct;20(10):965-974. doi: 10.1016/j.neo.2018.08.002. Epub 2018 Aug 25.

Dual BRD4 and AURKA Inhibition Is Synergistic against MYCN-Amplified and Nonamplified Neuroblastoma.

Author information

1
Nationwide Children's Hospital, Center for Childhood Cancer and Blood Disorders, 700 Children's Drive, Columbus, OH, 43205.
2
The Ohio State University, College of Arts and Sciences, 186 University Hall, Columbus, OH, 43210.
3
Nationwide Children's Hospital, Center for Childhood Cancer and Blood Disorders, 700 Children's Drive, Columbus, OH, 43205; The Ohio State University, College of Medicine, Department of Pediatrics, 370 W 9th Ave, Columbus, OH 43210. Electronic address: nilay.shah@nationwidechildrens.org.

Abstract

A majority of cases of high-risk neuroblastoma, an embryonal childhood cancer, are driven by MYC or MYCN-driven oncogenic signaling. While considered to be directly "undruggable" therapeutically, MYC and MYCN can be repressed transcriptionally by inhibition of Bromodomain-containing protein 4 (BRD4) or destabilized posttranslationally by inhibition of Aurora Kinase A (AURKA). Preclinical and early-phase clinical studies of BRD4 and AURKA inhibitors, however, show limited efficacy against neuroblastoma when used alone. We report our studies on the concomitant use of the BRD4 inhibitor I-BET151 and AURKA inhibitor alisertib. We show that, in vitro, the drugs act synergistically to inhibit viability in four models of high-risk neuroblastoma. We demonstrate that this synergy is driven, in part, by the ability of I-BET151 to mitigate reflexive upregulation of AURKA, MYC, and MYCN in response to AURKA inhibition. We then demonstrate that I-BET151 and alisertib are effective in prolonging survival in four xenograft neuroblastoma models in vivo, and this efficacy is augmented by the addition of the antitubule chemotherapeutic vincristine. These data suggest that epigenetic and posttranslational inhibition of MYC/MYCN-driven pathways may have significant clinical efficacy against neuroblastoma.

PMID:
30153557
PMCID:
PMC6111011
DOI:
10.1016/j.neo.2018.08.002
[Indexed for MEDLINE]
Free PMC Article

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