title: Effective inhibition of melanoma by BI-69A11 is mediated by dual targeting of the AKT and NF-κB pathways.
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.
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors: Yongmei
authors: Y
authors: Feng
authors: Elisa
authors: E
authors: Barile
authors: Surya K
authors: SK
authors: De
authors: John L
authors: JL
authors: Stebbins
authors: Apple
authors: A
authors: Cortez
authors: Pedro
authors: P
authors: Aza-Blanc
authors: Jessie
authors: J
authors: Villanueva
authors: Meenhard
authors: M
authors: Heryln
authors: Stan
authors: S
authors: Krajewski
authors: Maurizio
authors: M
authors: Pellecchia
authors: Ze'ev A
authors: ZA
authors: Ronai
authors: Gary G
authors: GG
authors: Chiang
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