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Previous studies have shown that Bromodomain and extraterminal (BET) inhibitors can inhibit <jats:italic>MYCN<\/jats:italic> expression and suppress <jats:italic>MYCN<\/jats:italic>\u2010amplified neuroblastoma in vivo. Furthermore, alterations within RAS\u2010MAPK (mitogen\u2010activated protein kinase) signaling play significant roles in neuroblastoma initiation, maintenance, and relapse, and mitogen\u2010activated extracellular signal\u2010regulated kinase (MEK)\u00a0inhibitors demonstrate efficacy in subsets of neuroblastoma preclinical models. Finally, hyperactivation of RAS\u2010MAPK signaling has been shown to promote resistance to BET inhibitors. Therefore, we examined the antitumor efficacy of combined BET\/MEK inhibition utilizing I\u2010BET726 or I\u2010BET762 and trametinib in high\u2010risk neuroblastoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>Utilizing a panel of genomically annotated neuroblastoma cell line models, we investigated the in vitro effects of combined BET\/MEK inhibition on cell proliferation and apoptosis. Furthermore, we evaluated the effects of combined inhibition in neuroblastoma xenograft models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Combined BET and MEK inhibition demonstrated synergistic effects on the growth and survival of a large panel of neuroblastoma cell lines through augmentation of apoptosis. A combination therapy slowed tumor growth in a non\u2010<jats:italic>MYCN<\/jats:italic>\u2013amplified, <jats:italic>NRAS<\/jats:italic>\u2010mutated neuroblastoma xenograft model, but had no efficacy in an <jats:italic>MYCN<\/jats:italic>\u2010amplified model harboring a loss\u2010of\u2010function mutation in <jats:italic>NF1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Combinatorial BET and MEK inhibition was synergistic in the vast majority of neuroblastoma cell lines in the in vitro setting but showed limited antitumor activity in vivo. Collectively, these data do not support clinical development of this combination in high\u2010risk neuroblastoma.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.28267","type":"journal-article","created":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T06:43:12Z","timestamp":1587364992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Limited antitumor activity of combined BET and MEK inhibition in neuroblastoma"],"prefix":"10.1002","volume":"67","author":[{"given":"Jason R.","family":"Healy","sequence":"first","affiliation":[{"name":"Division of Oncology and Center for Childhood Cancer Research Children's Hospital of Philadelphia  Philadelphia Pennsylvania"},{"name":"Department of Pharmacology and Experimental Therapeutics Thomas Jefferson University  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori 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