|Publication Type||Journal Article|
|Year of Publication||2009|
|Authors||Vasudevan, KM, Barbie, DA, Davies, MA, Rabinovsky, R, McNear, CJ, Kim, JJ, Hennessy, BT, Tseng, H, Pochanard, P, Kim, SY, Dunn, IF, Schinzel, AC, Sandy, P, Hoersch, S, Sheng, Q, Gupta, PB, Boehm, JS, Reiling, JH, Silver, S, Lu, Y, Stemke-Hale, K, Dutta, B, Joy, C, Sahin, AA, Gonzalez-Angulo, AM, Lluch, A, Rameh, LE, Jacks, T, Root, DE, Lander, ES, Mills, GB, Hahn, WC, Sellers, WR, Garraway, LA|
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.