DNA-PK, Nuclear mTOR, and the Androgen Pathway in Prostate Cancer.

Androgen and its receptor (AR) are major drivers of prostate cancer (PCa), a leading cause of mortality in aging men. Thus, understanding the numerous mechanisms by which AR can promote the growth and proliferation of PCa cells and enable their escape from hormone-dependent therapies, eventually leading to metastasis and death of the patient, is essential to discover alternative therapeutic approaches. Recently, two structurally related members of the phosphatidylinositol 3-kinase-like protein kinase (PIKK) family, DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR), were shown to have a direct role in modulating AR activity on chromatin of PCa cells. In this review, the common features of DNA-PK and mTOR and the similarities in their noncanonical roles as transcription coregulators of the AR are highlighted. An outlook on how these findings could be translated into new approaches to manage and treat PCa is provided.