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

Abstract

Neuroblastoma (NB) is one of the most common solid tumors in childhood. To date, targeting <i>MYCN</i>, a well-established driver gene in high-risk neuroblastoma, is still challenging. In recent years, inhibition of bromodomain and extra terminal (BET) proteins shows great potential in multiple of <i>Myc</i>-driven tumors. ARV-825 is a novel BET inhibitor using proteolysis-targeting chimera (PROTAC) technology which degrades target proteins by the proteasome. In this study, we investigated the effect of ARV-825 in neuroblastoma <i>in vitro</i> and <i>in vivo</i>. Our results showed that ARV-825 treatment robustly induced proliferative suppression, cell cycle arrest, and apoptosis in NB cells. Moreover, ARV-825 efficiently depleted BET protein expression, subsequently repressing the expression of <i>MYCN</i> or <i>c-Myc</i>. In the NB xenograft model, ARV-825 profoundly reduced tumor growth and led to the downregulation of BRD4 and <i>MYCN</i> expression in mice. Taken together, these findings provide evidence that PROTAC BET inhibitor is an efficient way to achieve <i>MYCN</i>/<i>c-Myc</i> manipulation, and ARV-825 can be used as a potential therapeutic strategy for the treatment of neuroblastoma.