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

Tomoko Tanaka, Mayumi Higashi, Koseki Kimura, Junko Wakao, Shigehisa Fumino, Tomoko Iehara, Hajime Hosoi, Toshiyuki Sakai, Tatsuro Tajiri

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2074-2079
Number of pages6
JournalJournal of Pediatric Surgery
Volume51
Issue number12
DOIs
Publication statusPublished - Dec 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Surgery

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