AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

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.

• Authors: 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 Lu, Katherine 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
• Journal: Cancer cell (Cancer Cell) Vol. 16 Issue 1 Pg. 21-32 (Jul 07 2009) ISSN: 1878-3686 [Electronic] United States
• PMID: 19573809 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• PDK1 protein, human
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• SGK3 protein, human
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Breast Neoplasms (enzymology, genetics, metabolism, physiopathology)
• Cell Line, Tumor
• Cell Survival (genetics)
• Class I Phosphatidylinositol 3-Kinases
• Enzyme Activation
• Female
• Gene Expression Profiling
• Humans
• Mutation
• Neoplasms (genetics, metabolism)
• PTEN Phosphohydrolase (deficiency, genetics)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, physiology)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Signal Transduction (genetics)