Preclinical Therapeutic Synergy of MEK1/2 and CDK4/6 Inhibition in Neuroblastoma

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