Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma

IF 2.9 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2024-11-05 DOI:10.1002/cam4.70082

Janith A. Seneviratne, Daenikka Ravindrarajah, Daniel R. Carter, Vicki Zhai, Amit Lalwani, Sukriti Krishan, Anushree Balachandran, Ernest Ng, Ruby Pandher, Matthew Wong, Tracy L. Nero, Shudong Wang, Murray D. Norris, Michelle Haber, Tao Liu, Michael W. Parker, Belamy B. Cheung, Glenn M. Marshall

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引用次数: 0

Abstract

Background

The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy.

Methods

We performed a high-throughput, combination chromatin-modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations.

Results

We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4-mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents.

Conclusion

Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.

Abstract Image

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联合抑制组蛋白甲基转移酶EZH2和DOT1L是治疗神经母细胞瘤的有效方法。

背景：儿童癌症--神经母细胞瘤（NB）的特点是突变发生率低，且具有较强的致癌胚胎驱动信号。许多新的靶向表观遗传修饰药物作为单一疗法在人体试验中均告失败：我们针对 NB 细胞进行了高通量、联合染色质修饰药物筛选。我们筛选了 13 种候选药物的 78 种独特组合：结果：我们发现两种组蛋白甲基转移酶（HMT）抑制剂的组合结果：我们发现两种组蛋白甲基转移酶（HMT）抑制剂的组合：靶向 EZH2 的 GSK343 和靶向 DOT1L 的 SGC0946，在 8 种 NB 细胞系中表现出最强的协同作用，而对正常成纤维细胞的毒性较低。NB 肿瘤样本中 EZH2 和 DOT1L 的高 mRNA 表达与最差的患者生存率相关。HMT抑制剂联合治疗可激活ATF4介导的内质网（ER）应激反应。此外，在质谱分析中，谷胱甘肽和几种氨基酸被HMT抑制剂联合使用所消耗。与单药相比，SGC0946和GSK343联合使用可减少肿瘤生长：我们的研究结果支持进一步研究 HMT 抑制剂组合作为 NB 的一种治疗方法。

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

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.