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 IBET-151 and AURKA inhibitor alisertib. We show that, in vitro, the drugs act synergistically to inhibit viability in three models of high-risk neuroblastoma. We demonstrate that this synergy is driven, in part, by the ability of IBET-151 to mitigate reflexive upregulation of AURKA, MYC, and MYCN in response to AURKA inhibition. We then demonstrate that IBET-151 and alisertib are effective in prolonging survival in three 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.

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

“…JQ1 treatment to repress BRD4 activity together with MLN8237 treatment synergistically promotes cell death in c-Myc expressing human glioblastoma cells [213]. Combined treatment with another BRD4 inhibitor, I-BET151, and alisertib is efficacious in exerting antitumor effects against neuroblastoma with or without MYCN amplification both in vitro and in vivo [214].…”

Targeting MYCN in Molecularly Defined Malignant Brain Tumors

“…Alisertib is a second generation, ATP competitive Aurora kinase A inhibitor, which inhibits autophosphorylation at T288. Combined Alisertib and BRD4 inhibition results in synergistic decrease of viability in high-risk, MYCN amplified NB cells ( 139 ). Alisertib shows also an advantage in pediatric GBM, where in vitro effects were observed in a number of patient-derived cells and in vivo , by prolonging mouse survival ( 140 ).…”

Anticancer Effects of I-BET151, an Inhibitor of Bromodomain and Extra-Terminal Domain Proteins

“…Inhibition of Aurora kinase A (AURKA) is an effective treatment, but treatment with an AURKA inhibitor (alisertib) often causes an upregulation of the transcription of AURKA, MYC, and MYCN. The combination of the AURKA inhibitor with I-BET151 significantly reduces the transcriptional upregulation and synergistically inhibits the tumor cell survival ( 94 ).…”