Abstract
BackgroundNeuroblastoma (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.MethodsIn 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.ResultsOur 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.ConclusionCollectively, our results provide evidence that cobimetinib, in combination with cis-RA, represents a feasible option to develop novel treatment strategies for refractory NB.
Highlights
Neuroblastoma (NB) is one of the most common childhood malignancies
Findings from these experiments show that cells with increased phosphorylated Mitogen-activated protein kinase kinase (MEK) were more sensitive to cobimetinib compared to those with less MEK1/2 phosphorylation (Fig. 2)
There was no significant difference in MEK1/2 activity between cells grown with serum and without serum suggesting that the growth factors found in serum do not have significant influence in the base-line MEK activity found in these cells in culture
Summary
Neuroblastoma (NB) is one of the most common childhood malignancies. High risk NB carries a poor outcome and significant treatment related toxicities and, has been a focus for new therapeutics research in pediatric oncology. Neuroblastoma (NB) is a malignancy of the embryonal sympathetic nervous system arising from neuroblasts and is the most common type of solid tumors in children [1]. Cure rates have improved over the past 20 years, event-free survival is still only about 45 % for patients with high-risk metastatic disease [2]. Heterogeneity is the hallmark of NB and its clinical behavior ranges from spontaneous regression to metastatic disease that is refractory to common therapies. To improve the clinical outcome of advanced NB, it is important to identify the key molecularly defined actionable pathways and targets for novel therapeutics in these patients
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