Abstract
Neuroblastoma (NB) is one of the most common solid tumors in childhood. To date, targeting MYCN, 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 Myc-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 in vitro and in vivo. 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 MYCN or c-Myc. In the NB xenograft model, ARV-825 profoundly reduced tumor growth and led to the downregulation of BRD4 and MYCN expression in mice. Taken together, these findings provide evidence that PROTAC BET inhibitor is an efficient way to achieve MYCN/c-Myc manipulation, and ARV-825 can be used as a potential therapeutic strategy for the treatment of neuroblastoma.
Highlights
Neuroblastoma (NB) is a common pediatric malignancy originating from the embryonic sympathetic nervous system, of which 90% of cases are diagnosed under age 5 [1, 2]
We examined the effect of proteolysis-targeting chimera (PROTAC) bromodomain and extra terminal (BET) inhibitor ARV-825 on neuroblastoma cell lines and xenograft mice model
MYCN amplification is regarded as an initiating event that drives the development of high-risk neuroblastomas [3]
Summary
Neuroblastoma (NB) is a common pediatric malignancy originating from the embryonic sympathetic nervous system, of which 90% of cases are diagnosed under age 5 [1, 2]. MYCN is regarded as one of the most. PROTAC BET Inhibitor ARV-825 in Neuroblastoma commonly validated genes implicated in NB tumorigenesis, which is amplified in about 50% of high-risk cases [3]. MYCN amplification strongly correlates to an undifferentiated, aggressive phenotype and indicates an adverse prognosis [4]. Targeting the Myc family protein, including N-Myc, is still challenging due to the lack of pockets that could be targeted directly with small molecules [5] For this reason, indirect targeting strategies are currently being explored to achieve Myc inhibition, which has become a promising therapeutic approach for these Myc-driven cancers
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