Background: The serine/threonine protein kinase, Akt, plays a key role in the modulation of cellular proliferation, tumour growth and survival through phosphorylation of different downstream molecules. Here we review the recent progress in studying roles of the phosphatydil-4-5-bisphosphate-3-kinase (PI3K)/Akt/mTOR pathway in prostate cancer (PCa) therapy, mainly focusing on the effects of inhibitors targeting this signalling pathway in the treatment of PCa to improve standard therapies in preclinical studies as well as the results of clinical trials in prostate cancers.
Methods: A computerised search was performed to identify all relevant studies in Medline. Additional articles were extracted based on recommendations from an expert panel of authors. This review summarizes the development of the compounds able to inhibit single elements of PI3K/Akt/mTOR pathways and provides the mechanism of action, pharmacokinetics and the available preclinical and clinical data. Furthermore, this review provides an overview of the market of treatments for recurrent or metastatic PCa.
Results: The activation of Akt triggers the mammalian target of rapamycin (mTOR) signaling pathways as an essential mechanism to escape the controls on proliferation and apoptosis following therapy. Phosphatase and tensin homolog (PTEN) is the central negative regulator of this cascade and is genetically and functionally silenced in PCa with high frequency. AKT relieves the negative regulation of mTOR to activate protein synthesis and cell proliferation through S6K and 4EBP1.
Conclusion: Accordingly, some PI3K, Akt and mTOR inhibitors have been tested as cancer therapeutic agents alone or in combination with standard therapies and showed sensitizing effects with radio-, hormoneand chemo-therapy.