Proven Benefits of Androgen Deprivation Therapy (ADT) in Combination with of Targeting PI3K/Akt/mTOR Signaling Pathway in Prostate Cancer

Introduction: Responsible for the survival, metastasis and therapeutic resistance of cancers, the mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and the phosphatidylinositol-3-kinase/Akt is one of the most commonly stimulated signaling pathways in cancers, including prostate cancer (CaP). Moreover, this pathway is the second key stimulator of PCa development after the pathway of androgen receptor (AR). Grown due to resistance to first line androgen deprivation therapy (ADT), castration-resistant prostate cancer (CRPC) is the fatal type of the disease.Methods: In this study, articles published in PubMed were searched to find appropriate English studies applying the keywords of prostate cancer, PI3K/Akt/mTOR inhibitor, ADT, castration-resistant prostate cancer, clinical trials and target therapy.Results: One of the factors that might be responsible for limited effectiveness of allosteric mTOR inhibitors in CRPC is the dynamic crosstalk that is currently revealed between PI3K/Akt/mTOR signaling pathways in PCa and androgen. It is suggested that efficacy and survival are enhanced by the therapies targeting this pathway since the development of prostate cancer to CRPC is mostly a consequence of somatic modifications in the PI3K/Akt/mTOR (mammalian target of rapamycin) pathway. According to preclinical data, the clinical inefficacy of mTOR inhibitors in CRPC was due to a reciprocal feedback mechanism between PI3K and androgen receptor signaling, which demonstrated that the androgen receptor might be more operational and there was a combinatorial targeting of mTORC1/2 and PI3K.Conclusion: One of the methods for overcoming or preventing castration resistance could be the integrated inhibition of PI3K and AR signaling. Therefore, it is crucial to discover novel techniques for reversing drug resistance for other main chemotherapeutic anticancer drugs by recognizing mechanisms that might obstruct drug resistance.

کلیدواژه ها:

prostate cancer ، PI3K/Akt/mTOR inhibitor ، ADT ، castration-resistant prostate cancer ، clinical trials and target therapy