Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target?

Although the prognosis of patients with localized prostate cancer is good after surgery, with a favorable response to androgen deprivation therapy, about one third of them invariably relapse, and progress to castration-resistant prostate cancer. Overall, prostate cancer therapies remain scarcely effective, thus it is mandatory to devise alternative treatments enhancing the efficacy of surgical castration and hormone administration. Dysregulation of the phosphoinositide 3-kinase pathway has attracted growing attention in prostate cancer due to the highly frequent association of epigenetic and post-translational modifications as well as to genetic alterations of both phosphoinositide 3-kinase and PTEN to onset and/or progression of this malignancy, and to resistance to canonical androgen-deprivation therapy. Here we provide a summary of the biological functions of the major players of this cascade and their deregulation in prostate cancer, summarizing the results of preclinical and clinical studies with PI3K signaling inhibitors and the reasons of failure independent from genomic changes. •Constitutive activation of the key PI3K/AKT/mTOR molecular hub is a hallmark of cancer.•Because of frequent PTEN deletion and PIK3CA mutation, PI3K signaling is a therapeutic target in prostate cancer.•Most PI3K/AKT/mTOR inhibitors did not reach or failed phase II as monotherapy.•Major drawbacks are compensatory mechanisms and PI3K/AR transcriptional cross-regulation.•Combined AKT and AR inhibition has recently emerged as a very encouraging CRPC strategy.