Combined therapy targeting AR and EZH2 curbs castration-resistant prostate cancer enhancing anti-tumor T-cell response.

IF 3 4区医学 Q2 GENETICS & HEREDITY Epigenomics Pub Date : 2024-03-26 DOI:10.2217/epi-2023-0374

Irene Fischetti, Laura Botti, Roberta Sulsenti, Valeria Cancila, Claudia Enriquez, Renata Ferri, Marco Bregni, Filippo Crivelli, Claudio Tripodo, Mario P Colombo, Elena Jachetti

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Abstract

Aim: 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. Methods: We investigated in vitro and in subcutaneous and spontaneous mouse models the effects of combining enzalutamide and GSK-126, a drug inhibiting the epigenetic modulator EZH2. Results: 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⁺ T lymphocytes. Conclusion: These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer.

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针对 AR 和 EZH2 的联合疗法可抑制阉割耐药前列腺癌，增强抗肿瘤 T 细胞反应。

目的：阉割耐药前列腺癌（CRPC）最终会对恩扎鲁胺等雄激素受体通路抑制剂产生耐药性。免疫疗法也在 CRPC 中失效。我们提出了一种新方法，可同时逆转恩杂鲁胺的耐药性和重启抗肿瘤免疫。方法：我们在体外、皮下和自发小鼠模型中研究了恩杂鲁胺与抑制表观遗传调节剂EZH2的药物GSK-126联用的效果。结果恩杂鲁胺和GSK-126能协同降低CRPC的生长，同时抑制肿瘤的神经内分泌分化。在免疫缺陷小鼠体内，这种抗肿瘤活性消失了。事实上，联合治疗可唤醒肿瘤特异性 CD8+ T 淋巴细胞的细胞毒性活性和 IFN-γ 生成。结论这些结果促进了恩杂鲁胺和GSK-126在CRPC中的联合应用，也为前列腺癌的免疫疗法提供了新途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Epigenomics GENETICS & HEREDITY-

CiteScore

5.80

自引率

2.60%

发文量

审稿时长

>12 weeks

期刊介绍： Epigenomics provides the forum to address the rapidly progressing research developments in this ever-expanding field; to report on the major challenges ahead and critical advances that are propelling the science forward. The journal delivers this information in concise, at-a-glance article formats – invaluable to a time constrained community. Substantial developments in our current knowledge and understanding of genomics and epigenetics are constantly being made, yet this field is still in its infancy. Epigenomics provides a critical overview of the latest and most significant advances as they unfold and explores their potential application in the clinical setting.