NMB

Combination of Trametinib with Navitoclax Enhances Apoptosis in RAS-MAPK-Mutated Cell Lines

Neuroblastoma is a pediatric tumor with variable prognosis. Relapsed tumors often have mutations in the RAS-MAPK pathway and are sensitive to MEK inhibitors in vitro, but these inhibitors alone do not lead to tumor regression in vivo. Eleveld et al. investigated the potential of combining MEK inhibitors with BCL-2 family inhibitors to improve therapeutic outcomes for neuroblastoma patients with RAS-MAPK mutations.

MEK inhibition typically reduces pERK and increases pMEK due to feedback loops. Trametinib, a MEK inhibitor, effectively decreased pERK in neuroblastoma cell lines, confirming on-target activity (Fig. 1C). However, increased levels of pMEK were observed with trametinib treatment in all cell lines except for NRAS-mutant SKNAS cells and wildtype NMB cells. Trametinib did not significantly kill RAS-MAPK-mutated neuroblastoma cells and mostly caused a plateau at higher concentrations. Treatment of trametinib with navitoclax significantly increased apoptosis. This was demonstrated by increased levels of cleaved caspase 3 and cleaved PARP (Fig. 1C). Bliss independence scores were calculated and showed synergy. Average bliss scores were 0.33 for RAS-mutated lines, 0.15 for NF1-mutated lines, and 0.34 for ALK-mutated lines. As controls, wildtype cell lines were used as they lack mutations in the RAS-MAPK pathway. Cell viability had no change with no cleaved caspase 3 or PARP detected and had a bliss score of 0.08 (Fig. 1C). This demonstrates that this combination is working better in cells with increased activity of the RAS-MAPK pathway.