gdc-0973 and Neuroblastoma

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.. 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.. 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.. Collectively, our results provide evidence that cobimetinib, in combination with cis-RA, represents a feasible option to develop novel treatment strategies for refractory NB.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Azetidines; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Extracellular Signal-Regulated MAP Kinases; Glial Fibrillary Acidic Protein; Humans; Isotretinoin; MAP Kinase Kinase 1; MAP Kinase Signaling System; Microtubule-Associated Proteins; Neuroblastoma; Piperidines; Proto-Oncogene Proteins c-raf