American Association for Cancer Research
10780432ccr161131-sup-165779_1_supp_3627628_cbyt97.pptx (14.93 MB)

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

Download (14.93 MB)
posted on 2023-03-31, 19:25 authored by Lori S. Hart, JulieAnn Rader, Pichai Raman, Vandana Batra, Mike R. Russell, Matthew Tsang, Maria Gagliardi, Lucy Chen, Daniel Martinez, Yimei Li, Andrew Wood, Sunkyu Kim, Sudha Parasuraman, Scott Delach, Kristina A. Cole, Shiva Krupa, Markus Boehm, Malte Peters, Giordano Caponigro, John M. Maris

Supplementary Figure S1. Neuroblastoma cell lines are sensitive to binimetinib. Supplementary Figure S2. Gene expression profiling of human neuroblastoma cell lines with regards to relative sensitivity to MEK1/2 and CDK4/6 inhibition Supplementary Figure S3. Combined MEK and CDK4/6 inhibition does not induce significant levels of apoptosis or senescence. Supplementary Figure S4. G1 arrest induced by MEK1/2 and CDK4/6 inhibition is reversible. Supplementary Figure S5. Gene expression profiling of human neuroblastoma cell lines with regards to the synergy observed from combined binimetinib-ribociclib treatment. Figure S6. Neuroblastoma xenografts are sensitive to combined binimetinib-ribociclib treatment.



Giulio D’Angio Endowed Chair

Cookies for Kids’ Cancer Foundation

Arms Wide Open Foundation

Rally Foundation

Alex's Lemonade Stand Foundation



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.