Senescence and castration resistance in prostate cancer: A review of experimental evidence and clinical implications

The development of Castration-Resistant Prostate Cancer (CRPC) remains a major challenge in the treatment of this disease. While Androgen Deprivation Therapy (ADT) can result in tumor shrinkage, a primary response of Prostate Cancer (PCa) cells to ADT is a senescent growth arrest. As a response to cancer therapies, senescence has often been considered as a beneficial outcome due to its association with stable growth abrogation, as well as the potential for immune system activation via the Senescence-Associated Secretory Phenotype (SASP). However, there is increasing evidence that not only can senescent cells regain proliferative capacity, but that senescence contributes to deleterious effects of cancer chemotherapy, including disease recurrence. Notably, the preponderance of work investigating the consequences of therapy-induced senescence on tumor progression has been performed in non-PCa models. Here, we summarize the evidence that ADT promotes a senescent response in PCa and postulate mechanisms by which senescence may contribute to the development of castration-resistance. Primarily, we suggest that ADT-induced senescence may support CRPC development via escape from senescence, by cell autonomous-reprogramming, and by the formation of a pro-tumorigenic SASP. However, due to the scarcity of direct evidence from PCa models, the consequences of ADT-induced senescence outlined here remain speculative until the relationship between senescence and CRPC can be experimentally defined.