Effective inhibition of melanoma by BI-69A11 is mediated by dual targeting of the AKT and NF-κB pathways

In melanoma, the activation of pro-survival signaling pathways, such as the AKT and NF-kappa B pathways, is critical for tumor growth. We have recently reported that the AKT inhibitor BI-69A11 causes efficient inhibition of melanoma growth. Here, we show that in addition to its AKT inhibitory activity, BI-69A11 also targets the NF-kappa B pathway. In melanoma cell lines, BI-69A11 inhibited TNF-alpha-stimulated IKK alpha/beta and I kappa B phosphorylation as well as NF-kappa B reporter gene expression. Furthermore, the effective inhibition of melanoma growth by BI-69A11 was attenuated upon NF-kappa B activation. Mechanistically, reduced NF-kappa B signaling by BI-69-A11 is mediated by the inhibition of sphingosine kinase 1, identified in a screen of 315 kinases. Significantly, we demonstrate that BI-69A11 is well tolerated and orally active against UACC 903 and SW1 melanoma xenografts. Our results demonstrate that BI-69A11 inhibits both the AKT and the NF-kappa B pathways and that the dual targeting of these pathways may be efficacious as a therapeutic strategy in melanoma.