# Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy

## TL;DR

This study shows that targeting specific pre-existing cells in prostate cancer can improve the effectiveness of androgen deprivation therapy.

## Contribution

The paper introduces a novel therapeutic strategy targeting castration-tolerant Club-like cells to enhance treatment outcomes in prostate cancer.

## Key findings

- Castration tolerance in LSCmed cells arises from transcriptional reprogramming, not intrinsic properties.
- Dual targeting of FOSL1/AP-1 and PIM kinases suppresses the growth of aggressive prostate cancer subtypes.
- FOSL1 gene expression is elevated in stem-like CRPC and is upregulated by enzalutamide treatment in high-risk patients.

## Abstract

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.

Although castration is the primary treatment for advanced prostate cancer, castration-resistant prostate cancer (CRPC) eventually develops in all patients. Here, we identify a therapeutic strategy that enhances the castration efficacy by targeting castration-tolerant cells in prostate tumors.

LSCmed cells, the mouse equivalent of human prostatic Club cells, exhibit high molecular similarity with human double negative prostate cancer subtypes lacking androgen receptor signature and neuroendocrine features (MSPC, CRPC-SCL).LSCmed cells respond to castration by a transcriptomic reprogramming orchestrated by the transcription factor FOSL1/AP-1, leading to increased aggressiveness.FOSL1 and FOSL1 target gene expression is elevated in stem-like-cell CRPC and is upregulated by neo-adjuvant enzalutamide monotherapy in patients with high-risk prostate cancer.Mouse and human Club-like cell proliferation, survival and progenitor properties, and CRPC growth in mice, are inhibited by combined pharmacological inhibition of FOSL1/AP-1 and PIM kinases.

LSCmed cells, the mouse equivalent of human prostatic Club cells, exhibit high molecular similarity with human double negative prostate cancer subtypes lacking androgen receptor signature and neuroendocrine features (MSPC, CRPC-SCL).

LSCmed cells respond to castration by a transcriptomic reprogramming orchestrated by the transcription factor FOSL1/AP-1, leading to increased aggressiveness.

FOSL1 and FOSL1 target gene expression is elevated in stem-like-cell CRPC and is upregulated by neo-adjuvant enzalutamide monotherapy in patients with high-risk prostate cancer.

Mouse and human Club-like cell proliferation, survival and progenitor properties, and CRPC growth in mice, are inhibited by combined pharmacological inhibition of FOSL1/AP-1 and PIM kinases.

Although castration is the primary treatment for advanced prostate cancer, castration-resistant prostate cancer (CRPC) eventually develops in all patients. Here, we identify a therapeutic strategy that enhances the castration efficacy by targeting castration-tolerant cells in prostate tumors.