Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

Abstract

The androgen receptor (AR) is the main therapeutic target in advanced prostate cancer, because it regulates the growth and progression of prostate cancer cells. Patients may undergo multiple lines of AR-directed treatments, including androgen-deprivation therapy, AR signaling inhibitors (abiraterone acetate, enzalutamide, apalutamide, or darolutamide), or combinations of these therapies. Yet, tumors inevitably develop resistance to the successive lines of treatment. The diverse mechanisms of resistance include reactivation of the AR and dysregulation of AR cofactors and collaborative transcription factors (TFs). Further elucidating the nexus between the AR and collaborative TFs may reveal new strategies targeting the AR directly or indirectly, such as targeting BET proteins or OCT1. However, appropriate preclinical models will be required to test the efficacy of these approaches. Fortunately, an increasing variety of patient-derived models, such as xenografts and organoids, are being developed for discovery-based research and preclinical drug screening. Here we review the mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery.

Phenotypic Characterization of Two Novel Cell Line Models of Castration Resistant Prostate Cancer

“…Here, we describe two novel cell lines which represent castration resistant sublines of the commonly used, androgen dependent prostate cancer cells lines LAPC4 and VCaP. It is worth noting that other groups have described similar models previously [34][35][36][37][38][39]61 . However, for many of these lines there is limited profiling data publicly available.…”

“…To help fill this need, we developed two novel CRPC cell line models which were derived from the commonly used prostate cancer cell lines, LAPC4 and VCaP 20,32,33 . Although castration resistant sublines of VCaP and LAPC4 have been used in prior studies, [34][35][36][37][38][39] . We therefore present a comprehensive characterization of LAPC4-CR and VCaP-CR models and delineate transcriptional and proteomic differences between castration resistant and parental, androgen dependent lines.…”

Undesirable Status of Prostate Cancer Cells after Intensive Inhibition of AR Signaling: Post-AR Era of CRPC Treatment

“…Other mutations, including T878A and F876L, show agonistic effects with treatment with AR antagonists flutamide and bicalutamide, respectively, as well as with new-generation AR antagonists such as enzalutamide [ 18 , 19 ]. Prominent AR mutations and their effects on AR activity are summarized well in another review [ 20 ].…”

High-Throughput Imaging Assay for Drug Screening of 3D Prostate Cancer Organoids

“…8,9 New therapies are required for these diverse forms of CRPC; however, preclinical development is often hampered by a shortage of patient-derived models and the limited ability to deploy them in drug screening. 10 Two of the most common ways in which human prostate cancer tissue is used in preclinical research is as patientderived xenografts (PDXs) and organoids. Serially transplantable PDXs are tumors that are continually transplanted in immunocompromised mice.…”