Interestingly, one study has reported that AKT-independent activation of mTORC1 following AKT inhibition can be overcome by combining AKT and mTORC1 inhibitors in a PTEN-deficient prostate cancer transgenic mouse model [206], supporting the concept of vertically targeting the PI3K–AKT–mTOR pathway to prevent drug resistance associated with PI3K–AKT–mTOR-directed monotherapies [180]. This evidence concerns the gene PIK3CA and Familial prostate cancer.