Comprehensive transcriptome, miRNA and kinome profiling identifies new treatment options for personalized lung cancer therapy

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2025-02-24 DOI:10.1002/ctm2.70177

Shen Zhong, Yvonne Börgeling, Patrick Zardo, Danny Jonigk, Jürgen Borlak

{"title":"Comprehensive transcriptome, miRNA and kinome profiling identifies new treatment options for personalized lung cancer therapy","authors":"Shen Zhong, Yvonne Börgeling, Patrick Zardo, Danny Jonigk, Jürgen Borlak","doi":"10.1002/ctm2.70177","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Basic research identified oncogenic driver mutations in lung cancer (LC). However, <10% of patients carry driver mutations. Thus, most patients are not recommended for first-line kinase inhibitor (KI)–based therapies. Through enabling technologies and bioinformatics, we gained deep insight into patient-specific signalling networks which permitted novel KI-based treatment options in LC.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We performed molecular pathology, transcriptomics and miRNA profiling across 95 well-characterized LC patients. We confirmed results based on cross-linked immunoprecipitation-sequencing data, and used <i>N</i> = 524 adeno- and 497 squamous cell carcinomas as validation sets. We employed the PamGene platform to identify aberrant kinases, validated the results by evaluating independent siRNA and CRISPR-mediated mRNA knockdown studies in human LC cell lines.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Transcriptomics revealed 439, 1240, 383 and 320 significantly upregulated genes, respectively, for adeno-, squamous, neuroendocrine and metastatic cases, and there are 1092, 1477, 609 and 1267 downregulated DEGs. Based on gene enrichment analysis and experimentally validated miRNA–gene interactions, we constructed regulatory networks specific for adeno-, squamous, neuroendocrine and metastatic LC. Molecular profiling discovered 137 significantly upregulated kinases (range 2–26-fold) of which 65 and 72, respectively, are tyrosine and serine-threonine kinases while 6 kinases carry driver mutations. Meanwhile, there are 21 kinases commonly upregulated irrespective of the histological type of LC. Bioinformatics decoded networks in which kinases function as master regulators. Typically, the networks consisted of 14, 9, 16 and 19 highly regulated kinases in adeno-, squamous, neuroendocrine and metastatic LC. Inhibition of kinases which function as master regulators disrupted the signalling networks, and their gene knock-down studies confirmed inhibition of cell proliferation in a panel of human LC cell lines. Additionally, the proposed molecular profiling enables KI-based therapies in patients with acquired drug resistance.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Our study broadens the perspective of KI-based therapies in LC, and we propose a framework to overcome acquired drug resistance.</p>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70177","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70177","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Basic research identified oncogenic driver mutations in lung cancer (LC). However, <10% of patients carry driver mutations. Thus, most patients are not recommended for first-line kinase inhibitor (KI)–based therapies. Through enabling technologies and bioinformatics, we gained deep insight into patient-specific signalling networks which permitted novel KI-based treatment options in LC.

Methods

We performed molecular pathology, transcriptomics and miRNA profiling across 95 well-characterized LC patients. We confirmed results based on cross-linked immunoprecipitation-sequencing data, and used N = 524 adeno- and 497 squamous cell carcinomas as validation sets. We employed the PamGene platform to identify aberrant kinases, validated the results by evaluating independent siRNA and CRISPR-mediated mRNA knockdown studies in human LC cell lines.

Results

Transcriptomics revealed 439, 1240, 383 and 320 significantly upregulated genes, respectively, for adeno-, squamous, neuroendocrine and metastatic cases, and there are 1092, 1477, 609 and 1267 downregulated DEGs. Based on gene enrichment analysis and experimentally validated miRNA–gene interactions, we constructed regulatory networks specific for adeno-, squamous, neuroendocrine and metastatic LC. Molecular profiling discovered 137 significantly upregulated kinases (range 2–26-fold) of which 65 and 72, respectively, are tyrosine and serine-threonine kinases while 6 kinases carry driver mutations. Meanwhile, there are 21 kinases commonly upregulated irrespective of the histological type of LC. Bioinformatics decoded networks in which kinases function as master regulators. Typically, the networks consisted of 14, 9, 16 and 19 highly regulated kinases in adeno-, squamous, neuroendocrine and metastatic LC. Inhibition of kinases which function as master regulators disrupted the signalling networks, and their gene knock-down studies confirmed inhibition of cell proliferation in a panel of human LC cell lines. Additionally, the proposed molecular profiling enables KI-based therapies in patients with acquired drug resistance.

Conclusions

Our study broadens the perspective of KI-based therapies in LC, and we propose a framework to overcome acquired drug resistance.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

综合转录组，miRNA和kinome分析确定了个性化肺癌治疗的新治疗选择

基础研究确定了肺癌（LC）的致癌驱动突变。然而，10%的患者携带驱动突变。因此，大多数患者不推荐一线激酶抑制剂（KI）为基础的治疗。通过使能技术和生物信息学，我们深入了解了患者特异性信号网络，从而允许在LC中采用新的基于ki的治疗方案。方法对95例特征明确的LC患者进行分子病理学、转录组学和miRNA分析。我们根据交联免疫沉淀测序数据证实了结果，并使用N = 524腺癌和497鳞状细胞癌作为验证集。我们使用PamGene平台鉴定异常激酶，并通过评估独立的siRNA和crispr介导的mRNA敲低在人LC细胞系中的研究来验证结果。结果在腺癌、鳞状癌、神经内分泌和转移性病例中，分别有439个、1240个、383个和320个基因显著上调，有1092个、1477个、609个和1267个基因下调。基于基因富集分析和实验验证的mirna -基因相互作用，我们构建了腺状、鳞状、神经内分泌和转移性LC的特异性调控网络。分子分析发现，137个激酶显著上调（范围2 - 26倍），其中65个和72个分别是酪氨酸激酶和丝氨酸-苏氨酸激酶，6个激酶携带驱动突变。与此同时，无论LC的组织学类型如何，都有21种激酶普遍上调。生物信息学解码的网络中，激酶的功能主要调控。通常，在腺、鳞状、神经内分泌和转移性LC中，这些网络由14、9、16和19个高度调控的激酶组成。抑制作为主要调节因子的激酶破坏了信号网络，它们的基因敲除研究证实了在一组人类LC细胞系中细胞增殖的抑制。此外，提出的分子谱分析使基于ki的治疗获得性耐药患者成为可能。我们的研究拓宽了基于ki的LC治疗的视角，并提出了克服获得性耐药的框架。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.