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J Pediatr Surg. 2016 Dec;51(12):2074-2079. doi: 10.1016/j.jpedsurg.2016.09.043. Epub 2016 Sep 16.

MEK inhibitors as a novel therapy for neuroblastoma: Their in vitro effects and predicting their efficacy.

Author information

1
Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
2
Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
3
Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan.
4
Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address: taji@koto.kpu-m.ac.jp.

Abstract

BACKGROUND:

A recent study reported that relapsed neuroblastomas had frequent RAS-ERK pathway mutations. We herein investigated the effects and pathways of MEK inhibitors, which inhibit the RAS-ERK pathway, as a new molecular-targeted therapy for refractory neuroblastomas.

METHOD:

Five neuroblastoma cell lines were treated with trametinib (MEK inhibitor) or CH5126766 (RAF/MEK inhibitor). Growth inhibition was analyzed using a cell viability assay. ERK phosphorylation and the MYCN expression were analyzed by immunoblotting or immunohistochemistry. RAS/RAF mutations were identified by direct sequencing or through the COSMIC database.

RESULTS:

Both MEK inhibitors showed growth inhibition effects on cells with ERK phosphorylation, but almost no effect on cells without. In immunoblotting analyses, ERK phosphorylation and MYCN expression were suppressed in ERK active cells by these drugs. Furthermore, phosphorylated-ERK immunohistochemistry corresponded to the drug responses. Regarding the relationship between RAS/Raf mutations and ERK phosphorylation, ERK was phosphorylated in one cell line (NLF) without RAS/Raf mutations.

CONCLUSION:

MEK inhibitors are a promising molecular-targeted therapeutic option for ERK active neuroblastomas. The efficacy of MEK inhibitors corresponds to ERK phosphorylation, while RAS/RAF mutations are not always detected in drug-sensitive cells. Phosphorylated-ERK immunohistochemistry is thus a useful method to analyze ERK activity and predict the therapeutic effects of MEK inhibitors.

KEYWORDS:

CH5126766; MEK inhibitor; Neuroblastoma; RAF/MEK inhibitor; RAS–ERK pathway; Trametinib

PMID:
27686482
DOI:
10.1016/j.jpedsurg.2016.09.043
[Indexed for MEDLINE]

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