Making the Case for Autophagy Inhibition as a Therapeutic Strategy in Combination with Androgen-Targeted Therapies in Prostate Cancer

SIMPLE SUMMARY: This paper is one in a series of articles that investigate the functional forms of autophagy induced in tumor cells in response to various chemotherapeutic modalities, with the overarching goal of determining whether autophagy targeting or modulation could serve as an effective adjuvant therapy. In this review, we focus on androgen-targeted therapies in prostate cancer, including androgen biosynthesis inhibitors and androgen receptor antagonists. ABSTRACT: Androgen receptor targeting remains the primary therapeutic strategy in prostate cancer, encompassing androgen biosynthesis inhibitors and androgen receptor antagonists. While both androgen-receptor-positive and “castration-resistant” prostate cancer are responsive to these approaches, the development of resistance is an almost inevitable outcome leading to the castration-resistant form of the disease. Given that “cytoprotective” autophagy is considered to be a predominant mechanism of resistance to various chemotherapeutic agents as well as to radiation in the cancer literature, the purpose of this review is to evaluate whether autophagy plays a central role in limiting the utility of androgen deprivation therapies in prostate cancer. Unlike most of our previous reports, where multiple functional forms of autophagy were identified, making it difficult if not impossible to propose autophagy inhibition as a therapeutic strategy, the cytoprotective form of autophagy appears to predominate in the case of androgen deprivation therapies. This opens a potential pathway for improving the outcomes for prostate cancer patients once effective and reliable pharmacological autophagy inhibitors have been developed.