# Androgen Receptor Point Mutations: A Mechanism of Therapeutic Resistance and a Framework for Rational Drug Design

## TL;DR

This review explains how mutations in the androgen receptor lead to drug resistance in prostate cancer and highlights the need for new drug design strategies.

## Contribution

The paper provides a structural and functional framework for understanding AR point mutations and their impact on drug resistance in prostate cancer.

## Key findings

- Point mutations in the androgen receptor's ligand-binding domain cause resistance to therapeutics by altering ligand-receptor interactions.
- Failure to inhibit the motility of the AF-2 region is a common mechanism of resistance across multiple drugs and mutations.
- Combination therapies using orthosteric and allosteric inhibitors are being explored, but none have reached clinical trials.

## Abstract

Point mutations in the androgen receptor ligand-binding domain are a clinical cause of drug resistance in castration resistant prostate cancer. This review examines how androgen receptor point mutations alter the structure of the ligand-binding domain and switch the function of some therapeutics from blocking receptor signaling to activating signaling. Structural studies demonstrate how point mutations change ligand–receptor interactions, with particular emphasis on changes that occur in the AF-2 region. Inability of ligands to inhibit the motility of the AF-2 region has been identified as the common cause of resistance across multiple clinical therapeutics and point mutations. To overcome resistance, researchers are exploring a combination of orthosteric and allosteric inhibitors and drugs targeting other receptor regions, although clinical translation has not been achieved. Critically, a deeper understanding of point mutations, supported by molecular docking and computational modeling, is essential for designing the next generation of androgen receptor targeting therapeutics.

Background: Point mutations to the androgen receptor (AR) ligand-binding domain (LBD) are becoming increasingly recognized as a mechanism of therapeutic resistance in castration resistant prostate cancer (CRPC). The present review explores how point mutations induce molecular changes that contribute to the eventual treatment failure of androgen receptor pathway inhibitors (ARPIs) in CRPC. Methods: The PubMed database was searched for structural studies on the AR LBD. Eligible articles included molecular docking analysis and emphasized changes in ligand–receptor interactions after point mutation. Structural data were obtained from the Protein Data Bank (PDB) using the search parameters “Androgen receptor ligand binding domain”, “Homo sapiens”, and “X-ray diffraction”. PDB files of wild-type and point mutant AR LBDs were accumulated for analysis. Results: A functional shift from inhibiting to activating AR has been documented for multiple ARPIs. Crystallography data and in silico evaluation have deciphered how changes in steric hindrance of the AF-2 domain contribute to ARPI loss of function. To combat therapeutic resistance, discovery efforts have begun to consider combination approaches of orthosteric and allosteric inhibitors, as well as compounds that target other AR domains. Although lead compounds have been identified, none have progressed into the clinic. Conclusions: Questions remain regarding the best approach for rationally designing new AR targeting therapeutics. Understanding how structural changes to the AR LBD lead to the failure of clinical therapeutics is a necessary step that should precede drug discovery campaigns. Moreover, computational modeling is a powerful tool that should be leveraged to streamline therapeutic development.