cancers Review Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer Wout Devlies 1,2 , Florian Handle 3 , Gaëtan Devos 2 , Steven Joniau 2 and Frank Claessens 1, *   Citation: Devlies, W.; Handle, F.; Devos, G.; Joniau, S.; Claessens, F. Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer. Cancers 2021, 13, 915. https://doi.org/10.3390/ cancers13040915 Academic Editors: Alfonso Urbanucci and Delila Gasi Tandefelt Received: 6 January 2021 Accepted: 16 February 2021 Published: 22 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Laboratory of Molecular Endocrinology, KU Leuven, 3000 Leuven, Belgium; wout.devlies@kuleuven.be 2 Department of Urology, University Hospitals Leuven, 3000 Leuven, Belgium; gaetan.devos@uzleuven.be (G.D.); steven.joniau@uzleuven.be (S.J.) 3 Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria; florian.handle@i-med.ac.at * Correspondence: frank.claessens@kuleuven.be Simple Summary: In this review, we will look into the existing methods to study treatment resistance to androgen receptor targeted therapies in prostate cancer. This will encompass both the different ex- isting preclinical models as well as the role specific models have played in the current understanding of resistance mechanisms. Abstract: Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies conse- quently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. This review looks into the current and future role of preclinical models to understand resistance to androgen receptor-targeted therapies. Increasing knowledge on this resistance will greatly improve insights into tumor pathophysiology and future treatment strategies in prostate cancer. Keywords: preclinical models; androgen receptor; prostate cancer; hormone treatment; ARSI; ARTA; treatment resistance 1. Introduction The androgen receptor (AR) is the main driver of proliferation in prostate cancer (PCa) cells, and thus is an important therapeutic target [1,2]. It consists of three structural components: the C terminal domain/ligand binding domain, the DNA binding domain, and the N terminal domain [3]. Ligand binding, dimerization, and complex formation with coregulators contribute to the downstream AR signaling [4] (Figure 1). At the cellular level, prostate epithelial cells depend on survival- and growth-inducing signals from the AR. Thus, AR inhibition deprives PCa cells of these signals and leads to G1 arrest [5]. Clinical targeting of the AR is achieved by LHRH agonists/antagonists and abi- raterone or by blocking the AR ligand binding pocket with anti-androgens (e.g., apa- lutamide, darolutamide, and enzalutamide). Unfortunately, curative treatment of ad- vanced PCa by these AR signaling inhibitors is prevented by the occurrence of resistance mechanisms [1,2]. To become resistant against these therapies, PCa cells have to overcome the lack of growth signals. The mechanisms can be broadly categorized into two groups: (1) mecha- nisms that reactivate AR signaling output (i.e., AR overexpression, mutation and splice variants, glucocorticoid receptor takeover, androgen synthesis); and (2) mechanisms that bypass the AR by providing growth signals via other means (i.e., alterations in cell cycle regulators, DNA repair pathways, PI3K/PTEN alterations, trans-differentiation into AR independent phenotypes such as neuroendocrine cells). Cancers 2021, 13, 915. https://doi.org/10.3390/cancers13040915 https://www.mdpi.com/journal/cancers