Synergistic Effect of Targeted Inhibition of MEK/ERK and PI3K/AKT Survival Signaling Pathways onInduction of Apoptosis in Melanoma

Objective The treatment of metastatic melanoma by conventional chemotherapeutic agents remains unsatisfactory. The present study was undertaken to reveal the role of co-inhibition of survival signaling pathways in apoptosis of melanoma cells. Methods A panel of human melanoma cell lines and fresh melanoma isolates was assessed for their sensitivity to the MEK inhibitor U0126 and/or AKT inhibitor LY294002. The proliferation and apoptosis of the cells were examined after treatment with the inhibitors. Results Constitutive activation of ERK1/2 and AKT was closely related to concentrations of serum in the culture medium (extracellular signals). The sensitivity of melanoma cells to apoptosis induced by inhibition of MEK/ERK was not correlated with the active BRAF mutation (BRAFV600E. Inhibition of MEK/ERK predominantly induced apoptosis; whereas inhibition of PI3K/AKT primarily inhibited proliferation. Co-inhibition of MEK/ERK1/2 and PI3K/AKT synergistically induced apoptosis. Conclusion Co-targeting MEK/ERK and PI3K/AKT pathways may further improve treatment for melanoma.