Abstract 4690: Inhibition of PI3K-AKT signaling causes a FOXO-dependent induction of receptor tyrosine kinase expression and phosphorylation in cancer

Hyperactivation of the PI3K-AKT-mTOR pathway is a common mechanism for oncogenic signaling in tumors and multiple inhibitors of this pathway are now in clinical development. As the PI3K-AKT-mTOR pathway is known to be tightly regulated by negative feedback, we hypothesized that these drugs might relieve feedback inhibition, reactivate upstream signaling and limit their antitumor effects. We tested the effects of inhibitors of PI3K and AKT kinase on receptor tyrosine kinase signaling in a panel of cell lines derived from multiple tumor types. PI3K-AKT pathway inhibition resulted in increased expression and phosphorylation of a common set of receptor tyrosine kinases, including IGF-1R and insulin receptor and HER3. Induction of RTK expression was dependent on activation of members of the Forkhead transcription factor family in response to AKT inhibition. We found that depletion of FOXO proteins blocked the rise in HER3, IGF-1R, and insulin receptor protein and phosphorylation caused by AKT inhibition. Expression of a constitutively activated form of one of the FOXO proteins resulted in increased expression of these receptors. Moreover, immunoprecipitation of FOXO proteins revealed that they are preferentially associated with the promoters of these receptors upon AKT inhibition. To determine the consequences of induction of these RTKs, we utilized HER kinase inhibitors to block activation of the receptors. In multiple xenograft tumor models, PI3K-AKT inhibition resulted in potent RTK induction in vivo and combined inhibition of the HER kinases and AKT resulted in improved antitumor effects with tumor regressions observed in several cases. We conclude that the PI3K-AKT pathway feedback regulates RTK expression through a FOXO-dependent induction of RTK transcripts. This reactivation of upstream RTK signaling is likely to attenuate the effects of AKT inhibition. Blockade of feedback-upregulated RTKs may significantly improve the antitumor effects of PI3K-AKT inhibitors and is a potential combination strategy for PI3K-AKT driven cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4690. doi:10.1158/1538-7445.AM2011-4690