AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer
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Author(s)
Sandy, Peter
Hoersch, Sebastian
Gupta, Piyush
Jacks, Tyler E
Lander, Eric Steven
Date Issued
July 2009
Journal
Cancer Cell
Publisher
Elsevier
Citation
Vasudevan, Krishna M., David A. Barbie, Michael A. Davies, Rosalia Rabinovsky, Chontelle J. McNear, Jessica J. Kim, Bryan T. Hennessy, et al. “AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer.” Cancer Cell 16, no. 1 (July 2009): 21–32. © 2009 Elsevier Inc.
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Final published version
Abstract
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1016/j.ccr.2009.04.012
