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

作者：Vasudevan Krishna M; Barbie David A; Davies Michael A; Rabinovsky Rosalia; McNear Chontelle J; Kim Jessica J; Hennessy Bryan T; Tseng Hsiuyi; Pochanard Panisa; Kim So Young; Dunn Ian F; Schinzel Anna C; Sandy Peter; Hoersch Sebastian; Sheng Qing; Gupta Piyush B; Boehm Jesse S; Reiling Jan H; Silver Serena; Lu Yiling; Stemke Hale Katherine; Dutta Bhaskar; Joy Corwin; Sahin Aysegul A; Gonzalez Angulo Ana Maria; Lluch Ana; Rameh Lucia E; Jacks Tyler

来源：Cancer Cell, 2009, 16(1): 21-32.

DOI：10.1016/j.ccr.2009.04.012

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.

• 出版日期2009-7-7