AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity Academic Article uri icon

Overview

MeSH Major

  • Feedback, Physiological
  • Gene Expression Regulation, Neoplastic
  • Proto-Oncogene Proteins c-akt
  • Receptor Protein-Tyrosine Kinases
  • Signal Transduction

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.

publication date

  • January 18, 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3025058

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2010.10.031

PubMed ID

  • 21215704

Additional Document Info

start page

  • 58

end page

  • 71

volume

  • 19

number

  • 1