EHMT1/2 inhibition promotes regression of therapy-resistant ovarian cancer tumors in a CD8 T cell-dependent manner.

IF 4.1 2区医学 Q2 CELL BIOLOGY

Molecular Cancer Research Pub Date : 2024-08-13 DOI:10.1158/1541-7786.MCR-24-0067

Lily L Nguyen, Zachary L Watson, Raquel Ortega, Elizabeth R Woodruff, Kimberly R Jordan, Ritsuko Iwanaga, Tomomi M Yamamoto, Courtney A Bailey, Francis To, Shujian Lin, Fabian R Villagomez, Abigail D Jeong, Saketh R Guntupalli, Kian Behbakht, Veronica Gibaja, Nausica Arnoult, Edward B Chuong, Benjamin G Bitler

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引用次数: 0

Abstract

Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising and there is currently an unmet need to combat PARPi-resistant tumors. Here, we created an immunocompetent, PARPi-resistant mouse model to test the efficacy of combinatory PARPi and euchromatic histone methyltransferase 1/2 inhibitor (EHMTi) in the treatment of PARPi-resistant ovarian cancer. We discovered that inhibition of EHMT1/2 resensitizes cells to PARPi. Markedly, we show that single EHMTi and combinatory EHMTi/PARPi significantly reduced PARPi-resistant tumor burden and that this reduction is partially dependent on CD8 T cells. Altogether, our results show a low-toxicity drug that effectively treats PARPi-resistant ovarian cancer in an immune-dependent manner, supporting its entry into clinical development and potential incorporation of immunotherapy. Implications: Targeting the epigenome of therapy-resistant ovarian cancer induces an anti-tumor response mediated in part through an anti-tumor immune response.

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EHMT1/2抑制以CD8 T细胞依赖的方式促进耐药卵巢癌肿瘤的消退。

聚 ADP 核糖聚合酶抑制剂（PARPi）是卵巢癌的一线维持疗法，也是其他几种癌症的替代疗法。然而，PARPi 耐药性正在上升，目前还没有满足抗 PARPi 耐药性肿瘤的需求。在此，我们创建了一种免疫功能正常的 PARPi 抗性小鼠模型，以测试 PARPi 和外色素组蛋白甲基转移酶 1/2（EHMTi）联合抑制剂治疗 PARPi 抗性卵巢癌的疗效。我们发现，抑制 EHMT1/2 可使细胞对 PARPi 重新敏感。我们发现，抑制EHMT1/2能使细胞对PARPi重新敏感。我们还发现，单药EHMTi和联合EHMTi/PARPi能显著减少PARPi耐药的肿瘤负荷，而这种减少部分依赖于CD8 T细胞。总之，我们的研究结果表明，一种低毒性药物能以免疫依赖的方式有效治疗 PARPi 耐药的卵巢癌，从而支持该药物进入临床开发阶段，并有可能纳入免疫疗法。意义：针对耐药卵巢癌的表观基因组诱导抗肿瘤反应，这种反应部分是通过抗肿瘤免疫反应介导的。

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

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.