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

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Abstract
In melanoma, the activation of pro‐survival signaling pathways, such as the AKT and NF‐κB 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‐κB pathway. In melanoma cell lines, BI‐69A11 inhibited TNF‐α‐stimulated IKKα/β and IκB phosphorylation as well as NF‐κB reporter gene expression. Furthermore, the effective inhibition of melanoma growth by BI‐69A11 was attenuated upon NF‐κB activation. Mechanistically, reduced NF‐κB 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‐κB pathways and that the dual targeting of these pathways may be efficacious as a therapeutic strategy in melanoma.

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