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- W2317143396 abstract "Abstract #3061 Background: Activation of the PI3K/Akt pathway is a common event in human cancers and is responsible for key aspects of the transformed phenotype. This pathway is activated in most breast cancers, but by different mechanisms including HER2 amplification, PI3K mutation and PTEN inactivation. Inhibition of this pathway is thus thought to be clinically useful, but the functional output of PI3K/Akt signaling and the corresponding clinical effects of its inhibition may be due to the mechanisms by which it is activated. The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy. Methodology/Principal Findings: Using a panel of human breast cancer cell lines that harbor HER2 amplification, PI3K or PTEN mutations, or wild-type of PI3K and PTEN, and a selective, PH-domain dependent, allosteric inhibitor of Akt1 and Akt2 (AKTi-1/2), and a variety of biochemical, molecular, and cellular techniques as well as in vivo xenograft models, we show that AKTi-1/2 resulted in the selective inhibition of breast tumor cell lines with either mutant PI3K or amplified HER2, but not those in which PI3K/Akt signaling is not mutationally activated. Cellular sensitivity was due to induction of G1 arrest and of apoptosis and associated with inhibition of Akt signaling, loss of D-cyclin expression, and dephosphorylation of Rb. Most importantly, AKTi-1/2 effectively inhibited Akt kinase and its downstream effectors in vivo and caused complete suppression of the growth of breast cancer xenografts with PI3K mutation or HER2 amplification, including models of the latter selected for resistance to Herceptin. Furthermore, chronic administration of the drug was well-tolerated, causing only transient hyperglycemia without gross toxicity to the host despite the pleiotropic normal functions of Akt. Conclusions/Significance: Our data demonstrate the exquisite dependence of PI3K-mutated or HER2-amplified breast cancer cells on Akt signaling, and that effective inhibition of Akt in tumors is feasible and effective in vivo. These findings suggest that direct inhibition of Akt may represent a therapeutic strategy for breast cancers that are addicted to the pathway and in patients with clinical resistance to Herceptin. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3061." @default.
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- W2317143396 date "2009-01-15" @default.
- W2317143396 modified "2023-09-28" @default.
- W2317143396 title "Breast tumor cells withPI3Kmutation orHER2amplification are selectively addicted to Akt signaling." @default.
- W2317143396 doi "https://doi.org/10.1158/0008-5472.sabcs-3061" @default.
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