Purpose: Neuroblastoma is treated with aggressive multimodal therapy, yet more 
than 50% of patients experience relapse. We recently showed that relapsed 
neuroblastomas frequently harbor mutations leading to hyperactivated ERK 
signaling and sensitivity to MEK inhibition therapy. Here we sought to define a 
synergistic therapeutic partner to potentiate MEK inhibition.Experimental 
Design: We first surveyed 22 genetically annotated human neuroblastoma-derived 
cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor 
binimetinib. After noting an inverse correlation with sensitivity to ribociclib 
(CDK4/6 inhibitor), we studied the combinatorial effect of these two agents 
using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse 
microscopy, and xenograft studies.Results: Sensitivity to binimetinib and 
ribociclib was inversely related (r = -0.58, P = 0.009). MYCN amplification 
status and expression were associated with ribociclib sensitivity and 
binimetinib resistance, whereas increased MAPK signaling was the main 
determinant of binimetinib sensitivity and ribociclib resistance. Treatment with 
both compounds resulted in synergistic or additive cellular growth inhibition in 
all lines tested and significant inhibition of tumor growth in three of four 
xenograft models of neuroblastoma. The augmented growth inhibition was 
attributed to diminished cell-cycle progression that was reversible upon removal 
of drugs.Conclusions: Here we demonstrate that combined binimetinib and 
ribociclib treatment shows therapeutic synergy across a broad panel of high-risk 
neuroblastoma preclinical models. These data support testing this combination 
therapy in relapsed high-risk neuroblastoma patients, with focus on cases with 
hyperactivated RAS-MAPK signaling. Clin Cancer Res; 23(7); 1785-96. ©2016 AACR.