One possible explanation for the inability of single-agent mTOR inhibitors to show efficacy in prostate cancer is the hypothesis that mTOR blockade leads to feedback-driven upregulation of signaling molecules upstream in the PI3K pathway. For example, rapamycin and rapalogs are primarily inhibitors of mTORC1 (mTOR in complex with raptor) but not mTORC2 (mTOR in complex with raptor). This might lead to compensatory phosphorylation of S473, one of the activation sites of AKT. Thus, there is a theoretical advantage of utilizing active site inhibitors of mTOR [11]. Seminal research by Carver et al. [12] has demonstrated the existence of bidirectional cross-talk between the PI3K pathway and androgen receptor (AR) signaling. For example, in a preclinical model, inhibition of the PI3K pathway resulted in activation of AR signaling in PTEN-deficient prostate cancer cells. Conversely, the AR antagonist enzalutamide appeared to upregulate AKT signaling by reducing levels of the regulatory phosphatase PHLPP. Moreover, combined blockade with the dual PI3K/mTOR inhibitor, BEZ235, administered together with enzalutamide led to reductions in tumor size in xenograft models of human prostate cancer that exceeded the effects seen with either agent used alone [12]. This work provides a sound rationale for simultaneous targeting of the androgen/AR pathway and the PI3K/mTOR pathway, a discovery that is beginning to be translated into the clinic (Table 17.1).