Text Wissenschaftlicher Artikel Open Access eng A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naïve tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSCmed (Lin-, Sca-1+, CD49fmed) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties, but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSCmed cells isolated from prostate-specific Pten-deficient (Ptenpc−/−) mice, we identify the emergence of castration-resistant LSCmed cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Ptenpc−/− LSCmed characteristics are prevalent in aggressive double-negative prostate cancer (DNPC) subtypes recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258—focused on FOSL1/AP-1 and PIM kinases, respectively—effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC. Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy Castration-Resistance Club Cells DNPC FOSL1 LSCmed Cells http://creativecommons.org/licenses/by/4.0/ application/pdf Documento PDF Articolo scientifico University of Veterinary Medicine Vienna. Shared Facility Bioinformatics and Biostatistics Manon Baurès (Shared Facility Bioinformatics and Biostatistics, Department of Biological Sciences and Pathobiology, Departments, University of Veterinary Medicine Vienna) Anne-Sophie Vieira Aleixo Emeline Pacreau (Clinical Department for Small Animals and Horses, Departments, University of Veterinary Medicine Vienna) Aysis Koshy Vanessa Friedrich Marc Diedisheim Martin Raigel Yichao Hua Charles Dariane Florence Boutillon Lukas Kenner (Clinical Department for Farm Animals and Food System Transformation, Departments, University of Veterinary Medicine Vienna) Jean-Christophe Marine Gilles Laverny Daniel Metzger Florian Rambow Jacques-Emmanuel Guidotti Vincent Goffin 2026 © The Author(s) open access doi:10.1038/s44321-026-00375-y Text journal article EMBO Molecular Medicine https://phaidra.vetmeduni.ac.at/o:5419