AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer

Krishna M. Vasudevan, David A. Barbie, Michael A. Davies, Rosalia Rabinovsky, Chontelle J. McNear, Jessica J. Kim, Bryan T. Hennessy, Hsiuyi Tseng, Panisa Pochanard, So Young Kim, Ian F. Dunn, Anna C. Schinzel, Peter Sandy, Sebastian Hoersch, Qing Sheng, Piyush B. Gupta, Jesse S. Boehm, Jan H. Reiling, Serena Silver, Yiling LuKatherine Stemke-Hale, Bhaskar Dutta, Corwin Joy, Aysegul A. Sahin, Ana Maria Gonzalez-Angulo, Ana Lluch, Lucia E. Rameh, Tyler Jacks, David E. Root, Eric S. Lander, Gordon B. Mills, William C. Hahn, William R. Sellers, Levi A. Garraway

Research output: Contribution to journalArticlepeer-review

445 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)21-32
Number of pages12
JournalCancer Cell
Issue number1
StatePublished - Jul 7 2009
Externally publishedYes



ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research


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