Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer

Abstract

Summary Prostate cancer is characterized by its dependence on androgen receptor and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival. Significance The two most frequently activated signaling pathways in prostate cancer are driven by AR and PI3K. Inhibitors of the PI3K pathway are in early clinical trials and AR inhibitors confer clinical responses in most patients. However, these inhibitors rarely induce tumor regression in preclinical models. Here we show that these pathways regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Therefore, tumor cells can adapt and survive when either single pathway is inhibited pharmacologically. Our demonstration of profound tumor regressions with combined pathway inhibition in preclinical prostate tumor models provides rationale for combination therapy in patients.

Association between serum levels of insulin‐like growth factor‐1, bioavailable testosterone, and pathologic Gleason score

“…The PI3K/AKT pathway is inhibited by phosphatase and tensin homolog (PTEN), which is a tumor suppressor 35. A previous study reported that complete loss of the PTEN gene is more frequent in high‐grade prostate cancer,36 in which, the PI3K/AKT pathway is constitutively active and requires minimal activation by IGF‐1 or other hormones.…”

A cancer pharmacogenomic screen powering crowd-sourced advancement of drug combination prediction

“…In some cases the biomarker rationale for AKT inhibitor synergy with RTK or MAPK inhibition was less direct and indicative of crosstalk and feedback signaling previously reported 31 . Interestingly antagonism was observed in cell lines harboring activating mutations of AR [32][33][34][35] . Feedback signaling resulting from AKT inhibition has been seen to drive AR activity which in turn can lead to the activation of the MAPK cascade 35,36 , attenuating respectively targeting drug activity.…”

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

“…The thermal cycling conditions were as follows: 95 C for 20 seconds followed by 40 cycles of 95 C for one second and 60 C for 20 seconds. To quantify the miRNA expression in the tumor tissues, we used the relative quantification (DDCt) method (13) with RNU6b serving as an internal control. RNA from PNF or LNCaP cells was always analyzed in parallel on the same reaction plate, and the expression of examined miRNAs in PNF or LNCaP cells was arbitrarily set to one.…”

“…The Pleckstrin homology domain and leucine rich repeat protein phosphatase (PHLPP) enzymes dephosphorylate the AKT kinase, which, in the phosphorylated state, induces cell growth. Loss of, or reduction of, PHLPP1 or PHLPP2 and the ensuing increase in phosphorylation of AKT is an established cause for induction and/or progression of prostate carcinoma (11)(12)(13). MiR-15a and miR-375, therefore, play important roles in prostate carcinoma and may represent potential therapeutic targets.…”