1. Doubling Down on mTOR Inhibition: Harnessing ZEBRA for Insights
Jason Yongsheng Chan, Yukti Choudhury, Min-Han Tan 
European Urology 
Volume 69, Issue 3, Pages (March 2016)
DOI: /j.eururo
Copyright © 2015 European Association of Urology Terms and Conditions

2. Fig. 1
(A) Steady-state feedback program elicited by activation of AKT and mTORC1. Receptor activation results in inhibitory feedback of IRS1 expression/stability through mTORC1, and inhibition of FOXO-mediated RTK (receptor tyrosine kinase) transcription via AKT activity. The result is attenuation of PI3K/AKT activity. (B) Rapalogs such as everolimus inhibit feedback inhibition through IRS1, resulting in persistent activation of PI3K/AKT signaling. (C) We hypothesize that dual inhibition of mTOR, as by AZD2014, inhibits mTORC2-mediated AKT activation, in addition to relieving feedback activation through mTORC1. This leads to FOXO-mediated transcription of RTKs and Rictor (a component of mTORC1), which eventually drives PI3K-AKT hyperactivity.
European Urology  , DOI: ( /j.eururo )
Copyright © 2015 European Association of Urology Terms and Conditions