Second generation androgen receptor antagonists and challenges in prostate cancer treatment

Abstract

Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due to this critical role of AR signaling in driving prostate cancer, therapy targeting the AR pathway has been the mainstay strategy for metastatic prostate cancer treatment. The utility of these agents has expanded with the emergence of second-generation AR antagonists, which began with the approval of enzalutamide in 2012 by the United States Food and Drug Administration (FDA). Together with apalutamide and darolutamide, which were approved in 2018 and 2019, respectively, these agents have improved the survival of patients with prostate cancer, with applications for both androgen-dependent and castration-resistant disease. While patients receiving these drugs receive a benefit in the form of prolonged survival, they are not cured and ultimately progress to lethal neuroendocrine prostate cancer (NEPC). Here we summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.

Fig. 1. The 2D structure of AR antagonists.

The red dotted box indicates the shared structure between drugs. Drug structure resources from PubChem (https://pubchem.ncbi.nlm.nih.gov/search/search.cgi).

Fig. 2. The binding location of AR antagonists and roles in inhibition of AR-mediated transactivation.

A All of the FDA-approved second-generation AR antagonists bind to the ligand-binding domain (LBD). Potential AR antagonists including proxalutamide (Prox), TRC253, BMS-641988, and SHR3680 bind to the LBD, while EPI-506 and EPI-7386 bind to the N-terminal domain (NTD). Among these AR antagonists, EPI-506 and EPI-7386, darolutamide, proxalutamide, and TRC253 can bind with AR harboring mutations such as F876L. B All of the AR antagonists that bind to the LBD can competitively inhibit DHT binding to AR, as well as AR nuclear translocation and binding to DNA and coactivators. Binding of EPI-506 and EPI-7386 to the NTD of AR can inhibit AR transcriptional activation. Of note, proxalutamide can also repress AR protein expression.

Fig. 3. Recurrent AR mutations and alternative splicing variants contribute to AR antagonist resistance.

Mutations in red are the most prevalent mutations in patients [74, 75], while those in black are enzalutamide- and apalutamide-resistant mutations [76, 77]. AR-v7 lacks exons 4/5/6/7/8 and differs by 16aa at the C-terminus compared with AR-FL. Exons 5/6/7 are excluded in AR^v567es compared with AR-FL.

Fig. 4. Mechanisms of resistance to androgen receptor inhibitors in prostate cancer.

The partial agonist role of second-generation AR antagonists induces the expression of cancer-related genes including GR. GR in turn regulates the expression of a set of genes that overlaps with AR downstream pathways. AR alterations can include alternative splicing, point mutation and overexpression. Other AR signaling-independent mechanisms such as PTEN/TP53/RB1 loss of function and MYCN/SOC2 activation can mediate CRPC progression and contribute to AR antagonist resistance in CRPC.