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

Journal of Experimental & Clinical Cancer Research

Aru Narendran¹  Tanya Tippett²  Yibing Ruan¹  Anjali Singh¹ 

[1] Division of Pediatric Oncology, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary T3B 6A8, Alberta, Canada;Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York 10065, NY, USA

关键词: Targeted therapy;    Differentiation;    Apoptosis;    Cobimetinib;    Neuroblastoma;   

Others  :  1226244
DOI  :  10.1186/s13046-015-0222-x

 received in 2015-05-21, accepted in 2015-09-11,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Singh et al.

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