cancers Review Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer Marzieh Ehsani, Faith Oluwakemi David and Aria Baniahmad * Institute of Human Genetics, Jena University Hospital, Am Klinikum 1, 07740 Jena, Germany; [email protected] (M.E.); [email protected] (F.O.D.) * Correspondence: [email protected]; Tel.: +49-3641-9396820 Simple Summary: Prostate cancer can develop under hormone treatment and chemotherapy from a castration-sensitive towards a castration-resistant into a drug resistant-tumor. The main hormonal drug target is the androgen receptor (AR). Androgen deprivation therapy reduces body-own andro- gen production and AR antagonists inhibit androgen-mediated activation of AR. Here, molecular mechanisms are described that review knowledge about tumor cells escape therapy by developing bypass mechanisms of AR-signaling. This includes genomic and non-genomic signaling. Deciphering the involved molecules that mediate castration and drug resistance will provide the basis of potential novel drug targets that may be used in addition to AR inhibition as combinatory treatment. Abstract: Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2–3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Citation: Ehsani, M.; David, F.O.; Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur Baniahmad, A. Androgen regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution Receptor-Dependent Mechanisms with selection upon therapy is presumably based on a high degree of tumor heterogenicity and Mediating Drug Resistance in plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and Prostate Cancer. Cancers 2021, 13, evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant 1534. https://doi.org/10.3390/ PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, cancers13071534 drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various Academic Editor: Patrizia Limonta acquired and intrinsic mechanisms that are AR-dependent and contribute to PCa drug resistance will be discussed. Received: 26 February 2021 Accepted: 20 March 2021 Keywords: androgen receptor; prostate cancer; AR antagonists; castration resistant PCa; androgen Published: 26 March 2021 deprivation therapy Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. 1.1. Role of AR in PCa and its Inhibition of AR in PCa Therapy Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of cancer deaths in males in Western countries [1]. PCa growth is regulated by the androgen receptor (AR), activated upon androgen binding [2]. AR is Copyright: © 2021 by the authors. not only essential for the development of the normal prostate gland but also promotes Licensee MDPI, Basel, Switzerland. the progression of PCa. Since most PCa at early diagnosis are androgen-dependent (also This article is an open access article termed castration-sensitive PCa (CSPC)) [3], inhibition of AR signaling by ADT is the distributed under the terms and first-line treatment. Although the original form of ADT is the surgical castration, currently conditions of the Creative Commons the chemical castration with ADT drugs, such as luteinizing hormone-releasing hormone Attribution (CC BY) license (https:// (LHRH) agonist or antagonists that reduce serum testosterone to castration levels, is creativecommons.org/licenses/by/ used [4]. However, unfortunately, within 30 months of persistent ADT, all PCa patients 4.0/). Cancers 2021, 13, 1534. https://doi.org/10.3390/cancers13071534 https://www.mdpi.com/journal/cancers CancersCancers2021 2021, 13, 13, 1534, x 22 of of 20 22 [4]. However, unfortunately, within 30 months of persistent ADT, all PCa patients even- eventuallytually develop develop resistance resistance to tocastration castration therapy therapy [5]. [5 ].This This stage stage is is referred referred to as castration-castration- resistantresistant PCa PCa (CRPC), (CRPC), where where patients patients display display increased increased serum serum PSA PSA levels levels in in serum serum despite despite ADT,ADT, suggesting suggesting a a dysregulated dysregulated activation activation of of AR AR signaling signaling [6 [6].]. Currently,Currently, CRPC CRPC patients patients are are additionally additionally treated treated with with AR-antagonists AR-antagonists such such as enzalu- as en- tamidezalutamide (Enz) (Enz) and darolutamideand darolutamide (ODM-201) (ODM-201 to fully) to blockfully theblock AR-axis. the AR-axis. The use The of use these of AR-antagoniststhese AR-antagonists shows shows long terms long benefits,terms benefi includingts, including significantly significantly lowering lowering serum serum PSA level,PSA decreaseslevel, decreases the risk the of metastasisrisk of metastasis and prolonged and prolonged overall survival overall insurvival CRPC patientsin CRPC [7 ,pa-8]. However,tients [7,8]. resistance However, occurs resistance eventually occurs alsoeven againsttually also AR against antagonist AR antagonist treatment resultingtreatment inresulting drug resistance in drug resistance PCa (DRPC), PCa (DRPC), mostly associated mostly associated with activation with activation of the AR-axis.of the AR-axis. The reactivationThe reactivation of AR of signaling AR signaling after long-termafter long-t inhibitionerm inhibition of AR-axis of AR-axis is partly is partly because because PCa cellsPCa slowlycells slowly develop develop multiple multiple adaptive adaptive mechanisms mechanisms of resistance of resistance in response in response to chronic to exposurechronic exposure to low testosterone to low testosterone and AR antagonistand AR antagonist environment. environment. However, However, AR remains AR anre- essentialmains an driver essential in this driver progression in this progression [6,9,10]. Thus, [6,9,10]. tumor Thus, evolution tumor seems evolution to be seems associated to be withassociated an adaptive with an response adaptive of response AR signaling of AR bypassing signaling bypassing ADT and antagonistADT and antagonist activity and ac- perhapstivity and selecting perhaps for selecting a more for aggressive a more aggres drug resistantsive drug CRPC resistant (Figure CRPC1). (Figure Until recently, 1). Until metastaticrecently, metastatic CRPC (mCRPC) CRPC lacked(mCRPC) effective lacked treatment effective options.treatment In options. this review, In this the review, molecular the mechanismsmolecular mechanisms leading to therapyleading to resistance therapy resistance against ADT against and ADT antagonists and antagonists and AR bypassand AR mechanismsbypass mechanisms as well as as adaptive well as adaptive signaling signaling of PCa will of PCa be discussed. will be discussed. CSPC CRPC DRPC AR-antagonists ADT Therapeutic drugs stem stem stem Reducing Enhancing drug other androgen-sensitive other resistant cells other cells NEPC Accumulation of genetic and epigenetic events Bypass mechanisms of AR-signaling FigureFigure 1.1. Schematic view view of of prostate prostate cancer cancer tumor tumor evol evolutionution upon upon therapy. therapy. In general, In general, due dueto ac- to cumulation of mutations, a tumor is composed of many cancer cell types leading to tumor cell accumulation of mutations, a tumor is composed of many cancer cell types leading to tumor cell heterogeneity. Cancer consists also of cancer stem cells (stem) and other non-cancerous cells heterogeneity. Cancer consists also of cancer stem cells (stem) and other non-cancerous cells (other, (other, including cancer -associated fibroblasts and immune cells). Androgen-deprivation therapy including(ADT) is mostly cancer -associatedsuccessful inhibiting fibroblasts the and growth immune of androgen-sensitive cells). Androgen-deprivation PCa cells. However, therapy (ADT) castra- istion-resistant mostly successful cells may inhibiting be selected the growthby the trea of androgen-sensitivetment and accumulate. PCa Trea cells.tment However, with AR castration- antago- resistantnists and cells other may therapeutic be selected drugs, by theincluding treatment chem andotherapy accumulate. and radiation, Treatment might with select AR antagonistsfor drug andresistant other PCa therapeutic cells leading drugs, to including a more aggressive chemotherapy tumor and (such radiation, as NEPC). might Associated select for with drug the resistant tumor PCaevolution, cells leading during to tumorigene a more aggressivesis PCa tumordevelops (such a variety as NEPC). of androgen Associated bypass with signaling. the tumor evolution, during tumorigenesis PCa develops a variety of androgen bypass signaling. Mechanistically, AR antagonists can induce cellular senescence in PCa cells in vitro as wellMechanistically, as ex vivo in patients AR antagonists PCa samples. can induce This indicates cellular senescencethat AR antagonists