Although we identify cancer patient-associated gain-of-function mutations in the PDK1 PH domain with a very rare (<1% of cases) compared with other components of PI3K-AKT pathway, these mutations either disturb S6K1-mediated PDK1 phosphorylation or block 14-3-3 binding the phosphorylated PDK1, also resulting in unleashing the inhibitory roles of S6K1 on PDK1/AKT signaling to exhibit oncogenic functions (Fig. 7c). This evidence concerns the gene PIK3CA and cancer.