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Cancer Cell. 2011 Jan 18;19(1):58-71. doi: 10.1016/j.ccr.2010.10.031. Epub 2011 Jan 6.

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

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1
Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

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.

PMID:
21215704
PMCID:
PMC3025058
DOI:
10.1016/j.ccr.2010.10.031
[Indexed for MEDLINE]
Free PMC Article

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