Limited antitumor activity of combined BET and MEK inhibition in neuroblastoma

• Type of Material: Article
• Authors: Jason R Healy, Childrens Hospital of Philadelphia; Lori S Hart, Childrens Hospital of Philadelphia; Alexander L Shazad, Childrens Hospital of Philadelphia; Maria E Gagliardi, Childrens Hospital of Philadelphia; Matthew Tsang, Childrens Hospital of Philadelphia; Jimmy Elias, Childrens Hospital of Philadelphia; Jacob Ruden, Childrens Hospital of Philadelphia; Alvin Farrel, Childrens Hospital of Philadelphia; Jo Lynne Rokita, Childrens Hospital of Philadelphia; Yimei Li, Childrens Hospital of Philadelphia; Anastasia Wyce, GlaxoSmithKline; Olena Barbash, GlaxoSmithKline; Vandana Batra, Childrens Hospital of Philadelphia; Minu Samanta, Childrens Hospital of Philadelphia; John M Maris, Childrens Hospital of Philadelphia; Robert Schnepp, Emory University
• Language: English
• Date: 2020-04-19
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/pbc.28267
• Title of Journal or Parent Work: PEDIATRIC BLOOD & CANCER
• Volume: 67
• Issue: 6
• Start Page: e28267
• End Page: e28267
• Grant/Funding Information: This work was supported in part by a research grant from GlaxoSmithKline (J.M.M.), NIH Grants R35 CA220500 (J.M.M.), K12 HD04324 (R.W.S), K08-7K08CA194162-02 (R.W.S.), T32GM008562 (J.R.H.), the Aflac Cancer and Blood Disorders Center Trust (R.W.S.), and the William G. Woods, MD, Aflac Clinical Investigator Chair (R.W.S).
• Keywords: Life Sciences & Biomedicine; BET; MEK; Science & Technology; Hematology; Oncology; MYCN; Pediatrics; MYC; EXPRESSION; ACTIVATING MUTATIONS; MAPK; THERAPEUTIC TARGET; CANCER; neuroblastoma; ALK KINASE; PROTEINS; RNAI SCREEN

Abstract

Background: The treatment of high-risk neuroblastoma continues to present a formidable challenge to pediatric oncology. Previous studies have shown that Bromodomain and extraterminal (BET) inhibitors can inhibit MYCN expression and suppress MYCN-amplified neuroblastoma in vivo. Furthermore, alterations within RAS-MAPK (mitogen-activated protein kinase) signaling play significant roles in neuroblastoma initiation, maintenance, and relapse, and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors demonstrate efficacy in subsets of neuroblastoma preclinical models. Finally, hyperactivation of RAS-MAPK signaling has been shown to promote resistance to BET inhibitors. Therefore, we examined the antitumor efficacy of combined BET/MEK inhibition utilizing I-BET726 or I-BET762 and trametinib in high-risk neuroblastoma. Procedure: 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. Results: 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-MYCN–amplified, NRAS-mutated neuroblastoma xenograft model, but had no efficacy in an MYCN-amplified model harboring a loss-of-function mutation in NF1. Conclusions: 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-risk neuroblastoma.