AR and PI3K/AKT in Prostate Cancer: A Tale of Two Interconnected Pathways

Abstract

Prostate cancer (PCa) is the most common cancer in men. The androgen receptor (AR) has a pivotal role in the pathogenesis and progression of PCa. Many therapies targeting AR signaling have been developed over the years. AR signaling inhibitors (ARSIs), including androgen synthesis inhibitors and AR antagonists, have proven to be effective in castration-sensitive PCa (CSPC) and improve survival, but men with castration-resistant PCa (CRPC) continue to have a poor prognosis. Despite a good initial response, drug resistance develops in almost all patients with metastatic CRPC, and ARSIs are no longer effective. Several mechanisms confer resistance to ARSI and include AR mutations but also hyperactivation of other pathways, such as PI3K/AKT/mTOR. This pathway controls key cellular processes, including proliferation and tumor progression, and it is the most frequently deregulated pathway in human cancers. A significant interaction between AR and the PI3K/AKT/mTOR signaling pathway has been shown in PCa. This review centers on the current scene of different AR and PI3K signaling pathway inhibitors, either as monotherapy or in combination treatments in PCa, and the treatment outcomes involved in both preclinical and clinical trials. A PubMed-based literature search was conducted up to November 2022. The most relevant and recent articles were selected to provide essential information and current evidence on the crosstalk between AR and the PI3K signaling pathways. The ClinicalTrials.gov registry was used to report information about clinical studies and their results using the Advanced research tool, filtering for disease and target.

Keywords: PI3K/AKT/mTOR; PTEN; androgen receptor signaling; combination therapy; prostate cancer.

Figure 1

Crosstalk between PI3K/AKT/mTOR and AR signaling pathways. The two signaling pathways are closely connected and regulated according to a reciprocal feedback mechanism. AR inhibition reduces FKBP5 levels, inhibiting PHLPP-mediated suppression of AKT, thereby activating AKT. Activation of AKT then generates upregulation of AR by several mechanisms, including direct phosphorylation of AR and nuclear exclusion of FOXO1. AKT: protein kinase B; AR: androgen receptor; ARE: androgen response element; FKBP5: FK506 binding protein 5; FOXO1: forkhead box transcription factor 1; GPCR: G-protein coupled receptor; mTOR: mammalian target of rapamycin; PIP3: phosphatidylinositol-3,4,5-triphosphate; PHLPP: PH domain of leucine repeat sequence-rich phosphatase; PSA: prostate-specific antigen; PTEN: phosphatase and tensin homolog; RTK: receptor tyrosine kinase.