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Limited antitumor activity of combined BET and MEK inhibition in neuroblastoma
Author(s) -
Healy Jason R.,
Hart Lori S.,
Shazad Alexander L.,
Gagliardi Maria E.,
Tsang Matthew,
Elias Jimmy,
Ruden Jacob,
Farrel Alvin,
Rokita Jo Lynne,
Li Yimei,
Wyce Anastasia,
Barbash Olena,
Batra Vandana,
Samanta Minu,
Maris John M.,
Schnepp Robert W.
Publication year - 2020
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.28267
Subject(s) - neuroblastoma , neuroblastoma ras viral oncogene homolog , cancer research , mapk/erk pathway , bromodomain , medicine , pediatric cancer , growth inhibition , in vivo , kinase , apoptosis , cell culture , cancer , biology , microbiology and biotechnology , epigenetics , kras , biochemistry , genetics , colorectal cancer , gene
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.