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      AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity.

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          Abstract

          Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.

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          Author and article information

          Journal
          Cancer Cell
          Cancer cell
          Elsevier BV
          1878-3686
          1535-6108
          Jan 18 2011
          : 19
          : 1
          Affiliations
          [1 ] Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
          Article
          S1535-6108(10)00433-2 NIHMS250123
          10.1016/j.ccr.2010.10.031
          3025058
          21215704
          5b8cb72c-fa81-49d0-92b2-55eb9df63389
          Copyright © 2011 Elsevier Inc. All rights reserved.
          History

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