Breast tumor cells with P13K mutation or HER2 amplification are selectively addicted to Akt signaling Journal Article
| Authors: | She, Q. B.; Chandarlapaty, S.; Ye, Q.; Lobo, J.; Haskell, K. M.; Leander, K. R.; DeFeo-Jones, D.; Huber, H. E.; Rosen, N. |
| Article Title: | Breast tumor cells with P13K mutation or HER2 amplification are selectively addicted to Akt signaling |
| Abstract: | Background: Dysregulated P13K/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 Findings: A 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/Significance: These 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. © 2008 She et al. |
| Keywords: | signal transduction; protein kinase b; controlled study; gene mutation; human cell; genetics; drug tolerability; dose response; drug dose comparison; nonhuman; pathophysiology; animal tissue; cell cycle; apoptosis; breast cancer; gene amplification; protein depletion; epidermal growth factor receptor 2; animal experiment; animal model; cancer cell culture; enzyme activation; tumor xenograft; drug effect; enzymology; pathology; tumor cell culture; tumor cells, cultured; breast neoplasms; phosphatidylinositol 3 kinase; physiology; cancer resistance; hyperglycemia; cancer inhibition; drug antagonism; dimethyl sulfoxide; breast tumor; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; cell cycle arrest; receptor, erbb-2; cycline; trastuzumab; drug sensitivity; cell cycle g1 phase; g1 phase; protein kinase b inhibitor; hyperinsulinemia; transient hyperglycemia; transient hyperinsulinemia |
| Journal Title: | PLoS ONE |
| Volume: | 3 |
| Issue: | 8 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2008-08-26 |
| Start Page: | e3065 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0003065 |
| PUBMED: | 18725974 |
| PROVIDER: | scopus |
| PMCID: | PMC2516933 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 64" - "Export Date: 17 November 2011" - "Source: Scopus" |
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