DOI: 10.6084/m9.figshare.25892580
title: Combined therapy targeting AR and EZH2 curbs castration-resistant prostate cancer enhancing anti-tumor T-cell response

description: <b>Aim:</b> Castration-resistant prostate cancer (CRPC) eventually becomes resistant to androgen receptor pathway inhibitors like enzalutamide. Immunotherapy also fails in CRPC. We propose a new approach to simultaneously revert enzalutamide resistance and rewire anti-tumor immunity. <b>Methods:</b> We investigated <i>in vitro</i> and in subcutaneous and spontaneous mouse models the effects of combining enzalutamide and GSK-126, a drug inhibiting the epigenetic modulator EZH2. <b>Results:</b> Enzalutamide and GSK-126 synergized to reduce CRPC growth, also restraining tumor neuroendocrine differentiation. The anti-tumor activity was lost in immunodeficient mice. Indeed, the combination treatment awoke cytotoxic activity and IFN-γ production of tumor-specific CD8<sup>+</sup> T lymphocytes. <b>Conclusion:</b> These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer. Prostate cancer depends on hormones called androgens for its growth. Therefore, hormonal therapies are commonly used. However, the tumor often does not respond to these treatments and new therapeutic approaches are needed. Here, using cell and mouse models, we have tested a new combination between hormone therapy and a drug that restrains an enzyme regulating gene expression. Our results have shown that this combination therapy not only reduces the growth of the tumor but also stops it from becoming more aggressive. This is really important because aggressive prostate cancer is much harder to treat. We have also found that this approach helps the immune system recognizing and attacking cancer cells. More research is needed to identify the mechanism of action of this treatment. However, our findings suggest that this approach could pave the way for new therapeutic strategies, including using immunotherapy, typically unsuccessful in treating prostate cancer. Castration-resistant prostate cancer is a fatal disease in which immunotherapy failed. Combined therapy inhibiting the androgen receptor and the epigenetic regulator EZH2 can revert castration resistance and promote anti-tumor immunity. Castration-resistant prostate cancer (CRPC) is initially responsive to androgen receptor pathway inhibitors, like enzalutamide, but resistance eventually occurs, often associated to the emergence of aggressive neuroendocrine prostate cancer. Immunotherapy showed no efficacy in prostate cancer so far due to the immunosuppressive microenvironment. We tested a new therapeutic approach combining enzalutamide and GSK-126, an inhibitor of the epigenetic regulator EZH2 in both <i>in vitro</i> and <i>in vivo</i> models of prostate cancer. GSK-126 treatment confers enzalutamide sensitivity to otherwise resistant prostate cancer cells. GSK-126 and enzalutamide combination blocks CRPC growth and neuroendocrine prostate cancer differentiation in mouse models. Antitumor efficacy of GSK-126 and enzalutamide combination is lost in immunodeficient mice. GSK-126 and enzalutamide combination restore the activity of tumor-specific CD8<sup>+</sup> T cells in the TRAMP spontaneous model. These results promote future clinical investigation of the combined use of enzalutamide and GSK-126 against CRPC and neuroendocrine prostate cancer, also opening new possibilities for immunotherapy in prostate cancer.