Administering testosterone at levels exceeding the physiological range, especially when alternated with anti-androgen therapy in men with metastatic castration-resistant prostate cancer (CRPC), has yielded notable benefits in clinical trials. As this approach becomes increasingly implemented in practice, it is essential to clarify how resistance develops. For this purpose, three distinct CRPC cell models responsive to testosterone were independently generated. From each model, lines resistant to high-dose testosterone (HTR) were selected. The three parental CRPC lines exhibited different sensitivities to elevated testosterone exposure in both in vitro and in vivo systems. The derived HTR variants showed stable resistance to testosterone and diverse responses to its withdrawal in animal studies. The variability in hormonal reaction corresponded to differences in androgen receptor (AR) expression within each cell population. These results present three HTR models suitable for probing the mechanisms underlying resistance to supraphysiologic testosterone and for exploring new therapeutic strategies.
