# Cell Models of Castration Resistant and High Dose Testosterone-Resistant Prostate Cancer Recapitulate the Heterogeneity of Response Observed in Clinical Practice

## TL;DR

Researchers created cell models of prostate cancer resistant to high-dose testosterone to study treatment resistance and find better therapies.

## Contribution

The development of three distinct cell models that recapitulate clinical resistance to high-dose testosterone in prostate cancer.

## Key findings

- Three CRPC cell lines showed differential responses to high-dose testosterone in vitro and in vivo.
- HTR lines were resistant to testosterone and showed varied responses to testosterone withdrawal.
- Heterogeneous responses correlate with varying levels of androgen receptor expression.

## Abstract

High dose testosterone therapy is emerging as a viable treatment strategy for metastatic castration-resistant prostate cancer. Although a significant minority of patients have a profound response to testosterone therapy, a majority show no response or have subsequent progression, highlighting the need for novel therapeutic strategies to enhance the efficacy of high dose testosterone therapy. We have developed heterogeneous cell models of castration-resistant and high dose testosterone-resistant prostate cancer that will allow for the identification of mechanisms of resistance and provide a pre-clinical vehicle for pharmacologic testing for this emerging clinical entity.

The use of supraphysiologic testosterone, particularly when alternated with an anti-androgen agent in men with metastatic castration-resistant prostate cancer (CRPC), has demonstrated promising results in clinical trials. As the use of this therapy in clinical practice is more widely adopted, there will be a growing need to understand the mechanisms of resistance. To that end, we independently derived three separate cell models of testosterone-sensitive CRPC. From each CRPC line, high dose testosterone-resistance (HTR) lines were selected. We demonstrated the differential response of the three CRPC lines to a high dose of testosterone in vitro and in vivo. We subsequently demonstrated the resistance of the HTR lines to testosterone and varying responses to testosterone withdrawal in vivo. The heterogeneity in responses to hormonal manipulation is correlated with varying levels of androgen receptor expression within the population. Overall, we show that we have developed three models of HTR that can be used to study the mechanisms of high dose testosterone resistance and identify potential therapeutic targets.