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