Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells.

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Singh A, Ruan Y, Tippett T, Narendran A

Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells.

J Exp Clin Cancer Res. 2015 Sep 18;34:104. doi: 10.1186/s13046-015-0222-x.

PubMed ID

26384788 [ View in PubMed

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Abstract

BACKGROUND: Neuroblastoma (NB) is one of the most common childhood malignancies. Currently, high risk NB carries a poor outcome and significant treatment related toxicities and, thus has been a focus for new therapeutics research in pediatric oncology. In this study, we evaluated the effects of the MEK inhibitor cobimetinib, as a single agent and in combinations, on the growth, survival and differentiation properties against a molecularly representative panel of NB cell lines. METHODS: In vitro anti-proliferative activity of cobimetinib alone or in combination was investigated by cell viability assays and its target modulatory activity was evaluated using phospho-kinases antibody arrays and western blot analysis. To determine the effect of combination with cis-RA on differentiation and resulting enhanced cellular cytotoxicity, the expression of glial fibrillary acidic protein (GFAP) and microtubule-associated protein 2 (MAP2) expression levels were examined by immuno-fluorescence. RESULTS: Our findings show that cobimetinib alone induced a concentration-dependent loss of cell viability in all NB cell lines. In addition, cobimetinib showed feedback activation of MEK1/2, and the dephosphorylation of extracellular signal-regulated kinases (ERK1/2) and c-RAF, providing information on the biological correlates of MEK inhibition in NB. Combined treatment with cis-RA, led to differentiation and enhanced sensitization of NB cells lines to cobimetinib. CONCLUSION: Collectively, our results provide evidence that cobimetinib, in combination with cis-RA, represents a feasible option to develop novel treatment strategies for refractory NB.

DrugBank Data that Cites this Article

Drugs

Cobimetinib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cobimetinib	Dual specificity mitogen-activated protein kinase kinase 1	Protein	Humans	Yes	Inhibitor	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Cobimetinib	Cytochrome P450 3A4	Protein	Humans	No	Substrate Inhibitor	Details