Targeting Pre-existing Club-Like Cells in Prostate Cancer Potentiates Androgen Deprivation Therapy

Baures, M.; Aleixo, A.-S. V.; Pacreau, E.; Koshy, A.; Diedisheim, M.; Raigel, M.; Hua, Y.; Dariane, C.; Boutillon, F.; Kenner, L.; Marine, J.-C.; Laverny, G.; Metzger, D.; Rambow, F.; Guidotti, J.-E.; Goffin, V.

doi:10.1101/2025.02.13.637653

bioRxiv · 10.1101/2025.02.13.637653

Targeting Pre-existing Club-Like Cells in Prostate Cancer Potentiates Androgen Deprivation Therapy

Baures, M.·Aleixo, A.-S. V.·Pacreau, E.·Koshy, A.·Diedisheim, M.·Raigel, M.·Hua, Y.·Dariane, C.·Boutillon, F.·Kenner, L.·Marine, J.-C.·Laverny, G.·Metzger, D.·Rambow, F.·Guidotti, J.-E.·Goffin, V.

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Abstract

A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naive 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.

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Baures, M., Aleixo, A.-S. V., Pacreau, E., Koshy, A., Diedisheim, M., Raigel, M., Hua, Y., Dariane, C., Boutillon, F., Kenner, L., Marine, J.-C., Laverny, G., Metzger, D., Rambow, F., Guidotti, J.-E., Goffin, V.. 2025-02-17. Targeting Pre-existing Club-Like Cells in Prostate Cancer Potentiates Androgen Deprivation Therapy. https://doi.org/10.1101/2025.02.13.637653

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