phaidra.vetmeduni.ac.at o:5419 DOI 10.1038/s44321-026-00375-y Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy 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. eng Castration-Resistance Club Cells DNPC FOSL1 LSCmed Cells 2026-08-13T09:51:21.807Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Baurès;Manon; FN:Manon Baurès END:VCARD BEGIN:VCARD VERSION:3.0 N:Vieira Aleixo;Anne-Sophie; FN:Anne-Sophie Vieira Aleixo END:VCARD BEGIN:VCARD VERSION:3.0 N:Pacreau;Emeline; FN:Emeline Pacreau END:VCARD BEGIN:VCARD VERSION:3.0 N:Koshy;Aysis; FN:Aysis Koshy X-ORCID:https://orcid.org/0009-0006-5478-8544 END:VCARD BEGIN:VCARD VERSION:3.0 N:Friedrich;Vanessa; FN:Vanessa Friedrich X-ORCID:https://orcid.org/0009-0007-4585-7971 END:VCARD BEGIN:VCARD VERSION:3.0 N:Diedisheim;Marc; FN:Marc Diedisheim X-ORCID:https://orcid.org/0000-0002-0418-1107 END:VCARD BEGIN:VCARD VERSION:3.0 N:Raigel;Martin; FN:Martin Raigel END:VCARD BEGIN:VCARD VERSION:3.0 N:Hua;Yichao; FN:Yichao Hua X-ORCID:https://orcid.org/0000-0002-1695-172X END:VCARD BEGIN:VCARD VERSION:3.0 N:Dariane;Charles; FN:Charles Dariane END:VCARD BEGIN:VCARD VERSION:3.0 N:Boutillon;Florence; FN:Florence Boutillon END:VCARD BEGIN:VCARD VERSION:3.0 N:Kenner;Lukas; FN:Lukas Kenner X-ORCID:https://orcid.org/0000-0003-2184-1338 END:VCARD BEGIN:VCARD VERSION:3.0 N:Marine;Jean-Christophe; FN:Jean-Christophe Marine END:VCARD BEGIN:VCARD VERSION:3.0 N:Laverny;Gilles; FN:Gilles Laverny X-ORCID:https://orcid.org/0000-0002-2666-6877 END:VCARD BEGIN:VCARD VERSION:3.0 N:Metzger;Daniel; FN:Daniel Metzger X-ORCID:https://orcid.org/0000-0002-5555-046X END:VCARD BEGIN:VCARD VERSION:3.0 N:Rambow;Florian; FN:Florian Rambow X-ORCID:https://orcid.org/0000-0002-9727-8986 END:VCARD BEGIN:VCARD VERSION:3.0 N:Guidotti;Jacques-Emmanuel; FN:Jacques-Emmanuel Guidotti X-ORCID:https://orcid.org/0000-0001-9285-8167 END:VCARD BEGIN:VCARD VERSION:3.0 N:Goffin;Vincent; FN:Vincent Goffin X-ORCID:https://orcid.org/0000-0002-8021-3086 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 12846702 https://phaidra.vetmeduni.ac.at/o:5419 https://phaidra.vetmeduni.ac.at/api/object/o:5419/thumbnail LOMv1.0 discipline