This project is based on the premise that aberrant activation of the PI3K/AKT pathway is a common featureof the dysregulated signaling network in human breast cancers and is responsible for key aspects of thetransformed phenotype. We have employed pharmacologic inhibitors of specific elements of this pathway tointerrogate its function and used the information obtained to develop novel clinical strategies. We havepreviously shown that the Hsp90 protein chaperone is required for the folding and stability of HER2 andAKT. In the first funding period, we showed that natural product inhibitors of Hsp90 induce HER2degradation and inhibit AKT activation in breast tumor cells with HER2 amplification. This leads to loss of Dcyclinexpression, G1 arrest, and differentiation of these tumors, in tissue culture and in vivo and sensitizesthem to taxanes and to inhibition of angiogenesis. This work led to phase 1 and phase 2 trials of the Hsp90inhibitor 17-AAG, which has now been shown to have significant antitumor activity in patients resistant toHerceptin (trastuzumab).These results and those of others suggest that Herceptin-resistant tumors remain dependent upon HER2signaling. We hypothesize that HER2 activation of PI3K/AKT signaling is necessary for their growth. Wenow propose to use experimental models of Herceptin-resistant breast cancer to determine the mechanismof this phenomenon, the role played by PI3K/AKT signaling, and the potential therapeutic value of Hsp90,PI3K, and AKT inhibitors in this setting. PI3K/AKT signaling is activated by a variety of mechanisms inbreast cancer: HER2 amplification, PI3K mutation, and decreased PTEN function are among the mostprominent. We now plan to use selective pharmacologic inhibitors of PI3K, AKT, and mTor to study thebiochemical and functional consequences of PI3K/AKT activation in each of these settings, to determine thefeasibility of inhibiting this pathway in vivo and to use these data to develop mechanism-based combinationtherapies that exploit the effects of inhibiting these targets.
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