Abstract
BackgroundDysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. 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 FindingsA selective allosteric inhibitor of Akt kinase was used to interrogate a panel of breast cancer cell lines characterized for genetic lesions that activate PI3K/Akt signaling: HER2 amplification or PI3K or PTEN mutations in order to determine the biochemical and biologic consequences of inhibition of this pathway. A variety of molecular techniques and tissue culture and in vivo xenograft models revealed that tumors with mutational activation of Akt signaling were selectively dependent on the pathway. In sensitive cells, pathway inhibition resulted in D-cyclin loss, G1 arrest and induction of apoptosis, whereas cells without pathway activation were unaffected. Most importantly, the drug 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/SignificanceThese data demonstrate that breast cancers with PI3K mutation or HER2 amplification are selectively dependent 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 and other cancers that are addicted to the pathway including tumors with resistant to Herceptin.
Highlights
The phosphatidylinositol 3-kinase (PI3K) enzyme family plays key roles in the transduction of metabolic, proliferative and survival signals induced by insulin and other growth factors [1]
The PI3K/Akt signaling pathway is deregulated in the majority of human cancers and almost certainly plays an important pathogenic role in carcinogenesis and progression
We show that a selective and potent allosteric inhibitor of Akt1 and Akt2 effectively inhibits Akt signaling in tumor bearing mice without gross toxicity or weight loss even when administered chronically (Figures 4 and 5 and S2)
Summary
The phosphatidylinositol 3-kinase (PI3K) enzyme family plays key roles in the transduction of metabolic, proliferative and survival signals induced by insulin and other growth factors [1]. PI3K signaling is activated by growth factor receptors and regulated and terminated by multiple factors including dephosphorylation of the 39phosphate of PIP3 by the phosphatase PTEN [2]. Amplification or overexpression of receptor tyrosine kinases occurs in many cancers [4,5] and activation of PI3K has been shown to be necessary for their ability to induce transformation. Activating mutations of the gene that encodes the catalytic subunit of class 1A PI3K (PIK3CA) have been identified in significant numbers of breast, colorectal and other tumors [6,7]. Dysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. 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
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