Biological & therapeutic implications of AKT & AR cooperation in advanced prostate cancer

Decreased PTEN function is a characteristic of advanced prostate cancer and leads to activation of the PI3K/AKT signaling pathway [1, 2]. We have used novel and selective allosteric inhibitors of AKT kinases to show that tumors including some prostate cancers with this pathway dysregulation are addicted to AKT signaling for the maintenance of transformation [3]. In addition, the AKT inhibitors effectively suppress tumor growth in vivo at tolerable inhibitor doses. In contrast, tumors with coexistent mutational activation of the RAS/RAF/MEK/ERK signaling pathway are resistant to AKT inhibition. In such tumors, inhibition of either pathway alone is insufficient to affect key downstream processes or to inhibit tumor growth. However, concurrent inhibition of both pathways effectively represses tumor growth in vivo, maximally induces apoptosis, and inhibits cap-dependent protein translation. Moreover, we recently discovered that the PI3K/AKT and RAS/ERK pathways cooperate to activate their common downstream targets; thus, they integrate function of both pathways in malignant transformation [4]. Whereas activation of PI3K/AKT signaling is a common event in prostate cancer, activation of ERK signaling by RAS or RAF mutation is rare [5, 6]. However, recent studies suggest that in prostate cancer, androgen- dependent activation of ETS transcriptional factor family members (e.g. ERG, ETV1) [7, 8] may play a similar role to RAS/RAF/ERK activated ETS factors in other carcinomas [9, 10]. Androgen receptor (AR)-driven ETS activation is commonly found in the majority of prostate cancer, including castration-resistant prostate cancer (CRPC) [7, 11, 12]. AR/ETS activation almost always coexists with activation of PI3K/AKT signaling, and both cooperate to promote prostate cancer progression [13, 14]. Our preliminary data revealed that AKT inhibition alone effectively suppressed growth of PTEN-deficient prostate cancer only in AR-negative tumors. In tumors with concurrent activation of both AR/ETS and PI3K/AKT pathways, we found that combined inhibition of AR and AKT synergistically induced apoptosis and markedly enhanced antitumor activity in vivo. Notably, we observed that expression of the anti-apoptotic protein survivin is regulated by both AKT and AR signaling, and that survivin is a dominant growth- promoting effector of that signaling. We hypothesize that AR-dependent ETS activation in prostate cancer reduces or eliminates any requirement for ERK signaling and cooperates with AKT activation to mediate many of the key aspects of the transformed phenotype. Thus, the cooperation of AR/ETS and PI3K/AKT signaling in prostate cancer may be functionally equivalent to the cooperation of MEK/ERK and PI3K/AKT signaling in other tumors (Fig.1). The central hypothesis of this project is that the AR/ETS and PI3K/AKT signaling pathways cooperate by convergent regulation of their common downstream targets; thus these targets integrate functions of both pathways in the growth and survival of prostate cancer. As such, combined inhibition of both pathways or targeting function of their common effectors would be an effective therapy for advanced prostate cancer. The overall goal of this project is to systematically determine the molecular mechanisms and genomic pathways underlying the cooperation of AKT and AR in prostate cancer progression and thereby develop a mechanism-based combination therapy with AKT and AR inhibitors for advanced prostate cancer.