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

Neoplasia : an International Journal for Oncology Research
Joshua FelgenhauerNilay Shah

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 ma...Continue Reading

Citations

Jun 13, 2019·Blood Advances·Carlos Murga-ZamalloaRyan A Wilcox
Nov 23, 2019·Cell Death & Disease·Matko ČančerFredrik J Swartling
Feb 16, 2021·Frontiers in Oncology·Anna BorgenvikFredrik J Swartling
Feb 26, 2021·Frontiers in Oncology·Zhihui LiuCarol J Thiele
May 11, 2021·Frontiers in Cell and Developmental Biology·Aleksandar KrsticDavid J Duffy
Jun 10, 2021·Neoplasia : an International Journal for Oncology Research·Joanna S YiW Clay Gustafson

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Methods Mentioned

BETA
xenograft
fluorescence imaging
scraping
xenografts

Software Mentioned

Compusyn
ImageQuant TL
GraphPad Prism

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