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

Abstract

Summary Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs commonly 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 phospho-protein 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.

Repression of cancer cell senescence by PKCι

“…Recent data show that activation of Akt downstream from mutant PIK3CA is not observed robustly in all cell types, further emphasizing the importance of additional downstream signaling events (Vasudevan et al, 2009). Although both PKCi and PKB/Akt are activated by PI-3-kinase signaling, there are potential differences in the details of their activation mechanism.…”

Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells

“…It is currently unclear whether AKT-independent myeloma cells are completely independent of PI3K-derived signals or whether other downstream signaling components, among them potentially SGK1, can substitute for AKT activity in these tumors. In this context, it is of particular interest that, using a broad panel of carcinoma cell lines, it has been demonstrated that in the absence of AKT activation PI3K transmits alternative signals to downstream substrates such as the SGK family member SGK3 (Vasudevan et al, 2009). Given these observations, it will be important to determine the exact contribution of both kinases, AKT and SGK1, to the malignant growth of myeloma cells.…”

mTOR-Dependent Cell Survival Mechanisms

“…However, in contrast to AKT, even basal SGK activity is controlled by mTORC2 because phosphorylation in its hydrophobic motif by mTORC2 is required for phosphorylation in the kinase domain by PDK1 (Garcia-Martinez and Alessi 2008). mTORC2 regulation of SGK could also have relevance in cancer cell survival as suggested by a recent study that finds SGK3 signaling (but not AKT signaling) downstream from PIK3CA mutations is essential for the survival of certain cancer cells (Vasudevan et al 2009). Thus, mTORC2 may regulate cell survival through both AKTdependent and AKT-independent pathways, although definitive mechanisms require further investigation.…”