PO.ET09.01 · 实验与分子治疗

NSD2的催化抑制在头颈鳞状细胞癌中显示出体外抗肿瘤活性

Catalytic inhibition of NSD2 demonstrates in vitro antitumor activity in head and neck squamous cell carcinoma

编号 4482 展板 1 时间 4/21 09:00–12:00 区域 Section 14 主讲 Amr Ismail, MD

分会场 Epigenetic Modulators 1

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作者与单位 Authors & Affiliations

Amr Ismail¹, Iuliia Topchu², Tingting Zhang³, Ahmed Ismail⁴, Peter Makhov⁵, Jia Xu⁶, Kang Le⁷, Michael Soth⁷, Yanis Boumber¹

¹Medicine - Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL,²Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation,³Department of Oncology, Shengli Oilfield Central Hospital, Dongying, China,⁴Medicine, Eastern Virginia Medical School at Old Dominion University, Norfolk, VA,⁵Fox Chase Cancer Center, Philadelphia, PA,⁶Genetics, University of Alabama at Birmingham, Birmingham, AL,⁷Institute for Applied Cancer Science, MD Anderson Cancer Center, Houston, TX

摘要 Abstract

中文摘要

NSD2是一种催化H3K36二甲基化的组蛋白甲基转移酶，在多种癌症中经常发生改变或过表达。近期研究表明，选择性NSD2催化抑制剂通过重编程染色质和转录状态，在胰腺癌和肺癌的临床前模型中抑制肿瘤生长。然而，NSD2催化抑制在其他实体瘤和血液系统恶性肿瘤中的作用尚不明确。我们实验室及其他实验室的先前研究表明，NSD2缺失会抑制HNSCC细胞生长。因此，我们在头颈鳞状细胞癌（HNSCC）JHU-11和FaDu细胞系以及携带NSD2激活突变的RPMI-8402急性淋巴细胞白血病（ALL）细胞系中，评估了一种高选择性NSD2抑制剂（IACS-17817）及其对映体（IACS-17818，作为阴性对照）的活性。细胞用递增浓度的抑制剂处理72小时，并在连续时间点用固定浓度的化合物处理细胞。然后通过蛋白质印迹法检测全局H3K36me2水平。IACS-17817以时间和浓度依赖性方式降低H3K36me2水平，在所有测试的细胞系中，处理72小时后，活性化合物浓度低至10 nM即出现显著下降。IACS-17817在HNSCC中最早24小时、在ALL细胞中最早48小时即出现作用起效。如克隆形成实验所示，NSD2抑制以时间和浓度依赖性方式抑制了HNSCC细胞的增殖。ALL RPMI-8402甲基纤维素细胞存活也正在评估中，结果尚待公布。如克隆形成实验所示，IACS-17817与PARP抑制剂olaparib的联合治疗在HNSCC细胞中相较于单药显示出相加的细胞毒性。这些发现将NSD2催化抑制的已知治疗范围从胰腺癌和肺癌扩展到头颈鳞状细胞癌（HNSCC），凸显了NSD2作为一个趋同性致癌驱动因素，并支持进一步开展NSD2靶向药物的临床前研发以推动临床转化。

查看英文原文 English abstract

NSD2 is a histone methyltransferase that catalyzes H3K36 dimethylation and is frequently altered or overexpressed in diverse cancers. Recent work has demonstrated that selective NSD2 catalytic inhibitors suppress tumor growth in preclinical models of pancreatic and lung cancer by reprogramming chromatin and transcriptional states. However, the effect of NSD2 catalytic inhibition in other solid and hematologic malignancies remains undefined. Prior studies from our lab and others demonstrated that NSD2 depletion suppresses HNSCC cell growth. We therefore evaluated the activity of a highly selective NSD2 inhibitor (IACS-17817) and its enantiomer (IACS-17818) as a negative control in head and neck squamous cell carcinoma (HNSCC) JHU-11 and FaDu cell lines, as well as in the RPMI-8402 acute lymphoblastic leukemia (ALL) cell line, which carries an NSD2-activating mutation. Cells were treated with escalating concentrations of the inhibitor for 72 hours, and cells were treated with a fixed concentration of the compounds at serial time points. Then, global H3K36me2 levels were tested via western blotting. IACS-17817 decreased H3K36me2 levels in a time and concentration-dependent manner, with a significant drop at treatment concentrations as low as 10 nM of the active compound after 72 hours in all cell lines tested. IACS-17817 showed an onset of action as early as 24 hours in HNSCC and 48 hours in ALL cells. NSD2 inhibition suppressed the proliferation of HNSCC cells as measured by clonogenic assays in a time- and concentration-dependent manner. ALL RPMI-8402 methylcellulose cell survival is also being evaluated, and results are pending. Combination treatment with IACS-17817 and the PARP inhibitor olaparib demonstrated additive cytotoxicity compared to single agents in HNSCC cells, as shown in clonogenic assays. These findings broaden the known therapeutic scope of NSD2 catalytic inhibition from pancreatic and lung cancers to head and neck squamous cell carcinoma (HNSCC), highlighting NSD2 as a convergent oncogenic driver and supporting further preclinical development of NSD2-targeting agents for clinical translation.

利益披露 Disclosure

A. Ismail, None.. I. Topchu, None.. T. Zhang, None.. A. Ismail, None.. P. Makhov, None.. J. Xu, None.. K. Le, None.. M. Soth, None.. Y. Boumber, None.

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