文章目录

用小分子靶向ADAR1治疗前列腺癌

原文发布日期：2025-02-10

英文摘要：

Despite the initial response to androgen signaling therapy, most cases of prostate cancer (PCa) eventually relapse and remain incurable. The specific function of ADAR1 that governs PCa progression and specific inhibitors of ADAR are underexplored. In this study, we demonstrate that highly expressed ADAR1 is a crucial oncogenic target in PCa and develop an effective small-molecule ADAR1 inhibitor, ZYS-1, with marked antitumor efficacy and a favorable safety profile. Either genetic or pharmacological inhibition of ADAR1 dramatically suppressed PCa growth and metastasis and potentiated the antitumor immune response. Moreover, ZYS-1 can enhance the antitumor effect of immunotherapy. We also reveal that ADAR1 represses the translation of MTDH in an editing-dependent manner, which drives cell proliferation and invasion in PCa. Collectively, our findings suggest that ADAR1 is a druggable target in PCa and highlight the widespread applicability of ADAR1 inhibitors for a broad spectrum of malignancies.

摘要翻译：

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文章：

用小分子靶向ADAR1治疗前列腺癌

Targeting ADAR1 with a small molecule for the treatment of prostate cancer

原文发布日期：2025-02-10

英文摘要：

Despite the initial response to androgen signaling therapy, most cases of prostate cancer (PCa) eventually relapse and remain incurable. The specific function of ADAR1 that governs PCa progression and specific inhibitors of ADAR are underexplored. In this study, we demonstrate that highly expressed ADAR1 is a crucial oncogenic target in PCa and develop an effective small-molecule ADAR1 inhibitor, ZYS-1, with marked antitumor efficacy and a favorable safety profile. Either genetic or pharmacological inhibition of ADAR1 dramatically suppressed PCa growth and metastasis and potentiated the antitumor immune response. Moreover, ZYS-1 can enhance the antitumor effect of immunotherapy. We also reveal that ADAR1 represses the translation of MTDH in an editing-dependent manner, which drives cell proliferation and invasion in PCa. Collectively, our findings suggest that ADAR1 is a druggable target in PCa and highlight the widespread applicability of ADAR1 inhibitors for a broad spectrum of malignancies.

摘要翻译：

尽管雄激素信号通路治疗对前列腺癌患者的初始反应良好，但大多数病例最终复发且不可治愈。与PCa进展调控和相关抑制剂相关的ADAR1的具体功能尚待深入探索。在本研究中，我们证明了高表达的ADAR1是前列腺癌的关键致癌目标，并开发了一种高效的小分子ADAR1抑制剂ZYS-1，其抗肿瘤效果显著且安全轮廓良好。无论从基因学还是药理学角度抑制ADAR1都会大幅抑制前列腺癌生长和转移，并增强抗肿瘤免疫应答。此外，ZYS-1还可以增强免疫疗法的抗肿瘤效果。我们还揭示了ADAR1通过依赖编辑介导的方式抑制MTDH翻译，从而驱动前列腺癌细胞增殖和侵袭。总的来说，我们的发现表明ADAR1是前列腺癌可靶向治疗的目标，并强调了基于ADAR1的广泛适用性药物在未来多种恶性肿瘤中的应用前景。