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

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.

PROTAC Bromodomain Inhibitor ARV-825 Displays Anti-Tumor Activity in Neuroblastoma by Repressing Expression of MYCN or c-Myc

“…The BET inhibitor BMS-986158 is currently under clinical trial in pediatric cancer, including neuroblastoma (NCT03936465). Furthermore, some studies described a combination therapy of BETi with other drugs has a synergistic effect against NB tumor progression (21,22).…”

BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells

“…As BET inhibition was shown to be synergistic with Aurora A inhibition in neuroblastoma cells 29 , we hypothesized that we could potentiate the effects of JQ1 on GBM cells by combining it with MLN8237. Similar to Felgenhauer et al 29 where they found synergism between BET and Aurora A inhibitors irrespective of MYCN status of neuroblastoma cells, we could demonstrate a strong synergism in all four tested GBM cell lines, irrespective of whether they had high (JQ1-sensitive) or low (JQ1-resistant) MYCN expression (Fig. 5d).…”

Effects of novel pyrrolomycin MP1 in MYCN amplified chemoresistant neuroblastoma cell lines alone and combined with temsirolimus

“…It does appear that the inhibition of the epigenetic regulator BRD-4 is not the mechanism by which MP1 inhibits MYCN given the lack of effect on gene or protein expression. This is an important observation given the early clinical use of BRD-4 inhibitors in MYCN amplified NB [22].…”