Jumonji组蛋白去甲基酶是小细胞肺癌癌症的治疗靶点-动脉网

Jumonji histone demethylases are therapeutic targets in small cell lung cancer

Nature 等信源发布 2024-08-18 11:37

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AbstractSmall cell lung cancer (SCLC) is a recalcitrant cancer of neuroendocrine (NE) origin. Changes in therapeutic approaches against SCLC have been lacking over the decades. Here, we use preclinical models to identify a new therapeutic vulnerability in SCLC consisting of the targetable Jumonji lysine demethylase (KDM) family.

摘要小细胞肺癌（SCLC）是一种神经内分泌（NE）起源的顽固性癌症。几十年来，针对SCLC的治疗方法一直缺乏变化。在这里，我们使用临床前模型来确定由可靶向的Jumonji赖氨酸脱甲基酶（KDM）家族组成的SCLC中的新治疗脆弱性。

We show that Jumonji demethylase inhibitors block malignant growth and that etoposide-resistant SCLC cell lines are particularly sensitive to Jumonji inhibition. Mechanistically, small molecule-mediated inhibition of Jumonji KDMs activates endoplasmic reticulum (ER) stress genes, upregulates ER stress signaling, and triggers apoptotic cell death.

我们显示Jumonji脱甲基酶抑制剂阻断恶性生长，并且依托泊苷抗性SCLC细胞系对Jumonji抑制特别敏感。从机制上讲，小分子介导的Jumonji KDM抑制激活内质网（ER）应激基因，上调ER应激信号传导，并触发凋亡细胞死亡。

Furthermore, Jumonji inhibitors decrease protein levels of SCLC NE markers INSM1 and Secretogranin-3 and of driver transcription factors ASCL1 and NEUROD1. Genetic knockdown of KDM4A, a Jumonji demethylase highly expressed in SCLC and a known regulator of ER stress genes, induces ER stress response genes, decreases INSM1, Secretogranin-3, and NEUROD1 and inhibits proliferation of SCLC in vitro and in vivo.

此外，Jumonji抑制剂降低SCLC-NE标记物INSM1和分泌素-3以及驱动转录因子ASCL1和NEUROD1的蛋白质水平。KDM4A是一种在SCLC中高度表达的Jumonji脱甲基酶，也是内质网应激基因的已知调节剂，其基因敲低可诱导内质网应激反应基因，降低INSM1，Secretogranin-3和NEUROD1，并在体外和体内抑制SCLC的增殖。

Lastly, we demonstrate that two different small molecule Jumonji KDM inhibitors (pan-inhibitor JIB-04 and KDM4 inhibitor SD70) block the growth of SCLC tumor xenografts in vivo. Our study highlights the translational potential of Jumonji KDM inhibitors against SCLC, a clinically feasible approach in light of recently opened clinical trials evaluating this drug class, and establishes KDM4A as a relevant target across SCLC subtypes..

最后，我们证明了两种不同的小分子Jumonji KDM抑制剂（泛抑制剂JIB-04和KDM4抑制剂SD70）在体内阻断SCLC肿瘤异种移植物的生长。我们的研究强调了Jumonji KDM抑制剂对SCLC的转化潜力，这是一种临床可行的方法，鉴于最近开放的评估该药物类别的临床试验，并将KDM4A确立为SCLC亚型的相关靶标。。

IntroductionSmall cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with poor prognosis because of rapid growth, early development of metastases, and acquired drug resistance [1]. Recently, immune checkpoint blockade immunotherapy has been approved for standard treatment with platin/etoposide, along with lurbinectedin for second-line treatment, yet overall median survival remains under 12 months, and therapy has changed little over several decades despite ongoing clinical trials to test new strategies [2,3,4,5,6].

引言小细胞肺癌（SCLC）是一种侵袭性神经内分泌恶性肿瘤，由于生长迅速，转移早期发展和获得性耐药，预后不良。最近，免疫检查点阻断免疫疗法已被批准用于铂/依托泊苷的标准治疗，以及用于二线治疗的lurbinectedin，但总体中位生存期仍不到12个月，尽管正在进行临床试验以测试新策略，但几十年来治疗几乎没有变化[2,3,4,5,6]。

Among all lung cancers, SCLC uniquely expresses high levels of neuroendocrine (NE) lineage transcription factors, including ASCL1 and/or NEUROD1 [5, 6]. Both of these lineage transcription factors promote the development and growth of neuroendocrine cells and have been shown to augment tumor growth and migration in SCLC [7, 8].

在所有肺癌中，SCLC独特地表达高水平的神经内分泌（NE）谱系转录因子，包括ASCL1和/或NEUROD1[5，6]。这两种谱系转录因子均促进神经内分泌细胞的发育和生长，并已被证明可增强SCLC中的肿瘤生长和迁移[7，8]。

In addition, distinct subsets of SCLC are driven by other factors including POU2F3 [9,10,11,12], although these are uncommon. SCLC tumors have a high mutational burden, almost universal loss of function of tumor suppressor genes RB1 and TP53, with the vast majority of patients having long-term exposure to tobacco carcinogens [12, 13].Platinum-etoposide chemotherapy has been the first-line treatment of SCLC since 1980 [14].

此外，SCLC的不同子集是由其他因素驱动的，包括POU2F3[9,10,11,12]，尽管这些并不常见。SCLC肿瘤具有高突变负担，几乎普遍丧失肿瘤抑制基因RB1和TP53的功能，绝大多数患者长期暴露于烟草致癌物[12，13]。自1980年以来，铂依托泊苷化疗一直是SCLC的一线治疗方法（14）。

Although in most patients this chemotherapy initially gives clinical and survival benefit, patients nearly always relapse with acquired chemoresistance [14, 15]. Unfortunately, only 20% of patients respond to second-line topotecan therapy, emphasizing the need to identify new treatment alternatives [16].

虽然在大多数患者中，这种化疗最初会带来临床和生存益处，但患者几乎总是复发并获得化疗耐药[14，15]。不幸的是，只有20%的患者对二线拓扑替康治疗有反应，强调需要确定新的治疗替代方案（16）。

In an effort to address this key knowledge gap, the National Cancer Institute evaluated 103 FDA-approved oncology drugs and 423 investigational agents in tests of a large panel of patient-derived SCLC.

为了解决这一关键知识差距，美国国家癌症研究所在一大批患者来源的SCLC测试中评估了103种FDA批准的肿瘤药物和423种研究药物。

Data availability

数据可用性

All data will be deposited publicly and made available and all reagents will be shared with the scientific community. RNA-seq data of untreated SCLC cells has been deposited at dbGaP under accession #phs001823.v1.p1. RNA-seq data of the H446 genetic series and of treated cells has been deposited at GEO (GSE208446)..

所有数据将公开保存并提供，所有试剂将与科学界共享。未经处理的SCLC细胞的RNA-seq数据已保存在dbGaP中，登录号为#phs001823.v1.p1。H446基因系列和处理细胞的RNA-seq数据已保存在GEO（GSE208446）。。

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Download referencesFundingThis work was supported by the Department of Defense (HT94252310012 to EDM), The Welch Foundation (I-1878 to EDM), the NIH (Lung Cancer SPORE P50 CA070907, U24 CA213274, U01 CA213338, CA142543 to JDM, R03CA273480 to EDM with a diversity supplement to CN), the Cancer Prevention and Research Institute of Texas Training grant (RP160157), and the UT Southwestern TARDIS Physician-Scientist Fellowship, which is funded by the Burroughs-Welcome Fund (RCh).

下载参考文献资助这项工作得到了国防部（EDM的HT94252310012），韦尔奇基金会（EDM的I-1878），NIH（肺癌孢子P50 CA070907，U24 CA213274，U01 CA213338，JDM的CA142543，EDM的R03CA273480以及CN的多样性补充），德克萨斯州癌症预防和研究所培训基金（RP160157）以及由Burroughs欢迎基金（RCh）资助的UT西南塔迪斯医师科学家奖学金的支持。

The authors thank the UT Southwestern Proteomics Core facility for help in performing proteomics experiments and acknowledge the helpful comments of current and former members of the Martinez and Minna laboratories including Dr. Juan Bayo-Fina.Author informationAuthors and AffiliationsHamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USAAiden Nguyen, Clarissa G.

作者感谢UT西南蛋白质组学核心设施在进行蛋白质组学实验方面的帮助，并感谢Martinez和Minna实验室现任和前任成员（包括Juan Bayo Fina博士）的有益评论。作者信息作者和附属机构德克萨斯州达拉斯UT西南医学中心萨蒙治疗肿瘤学研究中心，USAiden Nguyen，Clarissa G。

Nuñez, Tram Anh Tran, Luc Girard, Michael Peyton, Rodrigo Catalan, Cristina Guerena, Kimberley Avila, Benjamin J. Drapkin, Raghav Chandra, John D. Minna & Elisabeth D. MartinezDepartment of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USALuc Girard, John D. Minna & Elisabeth D. MartinezDepartment of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USABenjamin J.

努涅斯（Nuñez）、特拉姆·安·特拉恩（Tram Anh Tran）、吕克·吉拉德（Luc Girard）、迈克尔·佩顿（Michael Peyton）、罗德里戈·加泰罗尼亚（Rodrigo Catalan）、克里斯蒂娜·盖雷纳（Cristina Guerena）、金伯利·阿维拉（Kimberley Avila）、本杰明·J·德拉金（Benjamin J.Drapkin）、拉加夫·钱德拉（Raghav Chandra）、约翰·D·明纳（John D.Minna）和伊丽莎白·马丁内斯（Elisabeth D.Martinez）德克萨斯州达拉斯UT西南医学中心。

Drapkin & John D. MinnaSimmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USABenjamin J. Drapkin, John D. Minna & Elisabeth D. MartinezDepartment of Surgery, UT Southwestern Medical Center, Dallas, TX, USARaghav ChandraAuthorsAiden NguyenView author publicationsYou can also search for this author in.

Drapkin＆John D.Minnasimons综合癌症中心，德克萨斯州达拉斯UT西南医学中心Benjamin J.Drapkin，John D.Minna＆Elisabeth D.Martinez德克萨斯州达拉斯UT西南医学中心外科，USARaghav ChandraAuthorsAiden NguyenView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsAN performed many of the experiments analyzed data, and wrote parts of the manuscript. CN performed cell culture, Western blot, and drug response experiments, analyzed data, and wrote parts of the manuscript. TAT performed enzyme experiments, analyzed multiple datasets, and helped in figure design.

PubMed Google ScholarContributionsAN进行了许多实验，分析了数据，并撰写了部分手稿。CN进行了细胞培养，蛋白质印迹和药物反应实验，分析了数据，并撰写了部分手稿。TAT进行了酶实验，分析了多个数据集，并帮助进行了图形设计。

LG processed genomic data and performed hierarchical clustering and correlation analysis. MP performed some MTS experiments and provided input. KA performed some Western blots. RC performed some Western blots and cell experiments. CG performed Annexin IV assays with CN. RCh performed aspects of the in vivo work and edited parts of the manuscript.

LG处理基因组数据并进行层次聚类和相关性分析。MP进行了一些MTS实验并提供了输入。KA进行了一些蛋白质印迹。RC进行了一些蛋白质印迹和细胞实验。CG用CN进行了膜联蛋白IV测定。RCh进行了体内工作的各个方面并编辑了手稿的部分。

BD provided intellectual input and clinical insights. JDM guided aspects of the work and co-lead the project. EDM guided all aspects of the work, designed and analyzed experiments, co-lead the project, and wrote the manuscript.Corresponding authorCorrespondence to.

BD提供了智力投入和临床见解。JDM指导了工作的各个方面，并共同领导了该项目。EDM指导了工作的各个方面，设计和分析了实验，共同领导了项目，并撰写了手稿。对应作者对应。

Elisabeth D. Martinez.Ethics declarations

伊丽莎白·马丁内斯。道德宣言

Competing interests

相互竞争的利益

JDM receives royalties from the NIH and UTSW for the distribution of human tumor cell lines. None of the other authors have any competing interests to declare.

JDM从NIH和UTSW获得人类肿瘤细胞系分布的版税。其他作者都没有任何利益冲突。

Ethics approval

道德认可

All methods were performed in accordance with the relevant guidelines and regulations. All mouse studies were conducted under UTSW IACUC approval 2017-102260.

所有方法均按照相关指南和规定进行。所有小鼠研究均在UTSW IACUC批准2017-102260下进行。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary InformationSupplementary RNA-seq datasetRights and permissions

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充信息补充RNA-seq数据权限

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Reprints and permissionsAbout this articleCite this articleNguyen, A., Nuñez, C.G., Tran, T.A. et al. Jumonji histone demethylases are therapeutic targets in small cell lung cancer.

转载和许可本文引用本文Nguyen，A.，Nuñez，C.G.，Tran，T.A。等人。Jumonji组蛋白脱甲基酶是小细胞肺癌的治疗靶点。

Oncogene (2024). https://doi.org/10.1038/s41388-024-03125-xDownload citationReceived: 10 January 2024Revised: 30 July 2024Accepted: 06 August 2024Published: 18 August 2024DOI: https://doi.org/10.1038/s41388-024-03125-xShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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