PD11-09 CELLULAR MECHANISMS OF 5-ALPHA REDUCTASE INHIBITOR TREATMENT RESISTANCE IN BENIGN PROSTATIC HYPERPLASIA

Abstract

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD11)1 Sep 2021PD11-09 CELLULAR MECHANISMS OF 5-ALPHA REDUCTASE INHIBITOR TREATMENT RESISTANCE IN BENIGN PROSTATIC HYPERPLASIA Diya Binoy Joseph, Gervaise Henry, Alicia Malewska, Jeffrey Reese, Ryan Mauck, Jeffrey Gahan, Ryan Hutchinson, James Mohler, Claus Roehrborn, and Douglas Strand Diya Binoy JosephDiya Binoy Joseph More articles by this author , Gervaise HenryGervaise Henry More articles by this author , Alicia MalewskaAlicia Malewska More articles by this author , Jeffrey ReeseJeffrey Reese More articles by this author , Ryan MauckRyan Mauck More articles by this author , Jeffrey GahanJeffrey Gahan More articles by this author , Ryan HutchinsonRyan Hutchinson More articles by this author , James MohlerJames Mohler More articles by this author , Claus RoehrbornClaus Roehrborn More articles by this author , and Douglas StrandDouglas Strand More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001986.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 5-alpha reductase inhibitors (5ARIs) are prescribed to reduce prostate volume and alleviate lower urinary tract symptoms due to Benign Prostatic Hyperplasia (BPH). In some patients, prostate shrinkage is focal and does not result in improved urinary symptoms. We examined the phenotypic changes in glandular acini accompanying 5ARI treatment to determine the cellular mechanisms of treatment resistance. METHODS: Mass spectrometry was performed to measure 5ARI drug and hormone levels in prostate tissue from BPH patients. Patients with confirmed presence of 5ARI drug, low DHT and histological response were selected for spatial transcriptomics. Visium spatial transcriptomics was performed on histologically-responsive and non-responsive regions. Primary prostate epithelial cells were treated with TNF-α to activate NF-κB and qPCR was used to measure lineage-specific gene expression. RESULTS: We observed that patients with detectable levels of 5ARI drug display reduced DHT and increased testosterone regardless of phenotypic response. In 5ARI treated patients, regions of normal prostate glandular architecture can often be seen adjacent to regions of smaller acini with multiple cell layers, defined as histologically-resistant and -responsive, respectively. Spatial transcriptomics performed on histologically-resistant vs. -responsive regions revealed a urethral club-like molecular signature in small acini. These regions displayed increased TNF-α expression and nuclear localization and phosphorylation of p65. Treatment of primary prostate epithelial cells with TNF-α activated NF-κB and upregulated club cell genes, recapitulating the in vivo expression of these genes in responsive regions. CONCLUSIONS: We conclude that 5ARI treatment results in small ducts of androgen-independent club cells. It is unclear whether 5ARI treatment is inducing direct lineage switching of prostate luminal cells to club-like cells for survival or whether 5ARI-induced apoptosis of prostate luminal cells is indirectly driving altered differentiation of basal epithelia to club epithelia. Alternatively, androgen-independent club cells may be expanded during BPH and survive 5ARI treatment and repopulate prostate glands after 5ARI withdrawal. Further studies are required to determine how adjacent, histologically normal prostate glands maintain AR-dependent signaling despite low levels of tissue DHT and whether club cells can act as progenitors during androgen replenishment and prostate regrowth. Source of Funding: AUA Research Scholar Award 659333 to DBJ, R01 DK115477 to DWS and NCI P30CA016056 to Roswell Park Comprehensive Cancer Center for support of the Bioanalytical, Metabolomics, and Pharmacokinetics Shared Resource © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e201-e201 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Diya Binoy Joseph More articles by this author Gervaise Henry More articles by this author Alicia Malewska More articles by this author Jeffrey Reese More articles by this author Ryan Mauck More articles by this author Jeffrey Gahan More articles by this author Ryan Hutchinson More articles by this author James Mohler More articles by this author Claus Roehrborn More articles by this author Douglas Strand More articles by this author Expand All Advertisement Loading ...