Unveiling unique protein and phosphorylation signatures in lung adenocarcinomas with and without ALK, EGFR, and KRAS genetic alterations.

IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Fanni Bugyi, Mirjam Balbisi, Simon Sugár, Lóránd Váncza, Eszter Regős, Ilona Kovalszky, Ibolya Laczó, Tünde Harkó, Gábor Kecskeméti, Zoltán Szabó, Judit Moldvay, László Drahos, Lilla Turiák
{"title":"Unveiling unique protein and phosphorylation signatures in lung adenocarcinomas with and without ALK, EGFR, and KRAS genetic alterations.","authors":"Fanni Bugyi, Mirjam Balbisi, Simon Sugár, Lóránd Váncza, Eszter Regős, Ilona Kovalszky, Ibolya Laczó, Tünde Harkó, Gábor Kecskeméti, Zoltán Szabó, Judit Moldvay, László Drahos, Lilla Turiák","doi":"10.1002/1878-0261.70091","DOIUrl":null,"url":null,"abstract":"<p><p>Genetic alterations in key oncogenes have been frequently identified in lung adenocarcinoma (LUAD), including genes encoding epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK). In this pilot study, we aimed to characterize the differences in enriched biological pathways and phosphorylation events between LUAD tumors harboring EGFR, KRAS, or echinoderm microtubule-associated protein-like 4 (EML4)-ALK oncogenic alterations and triple wild-type LUAD tumors (WT, without EML4-ALK, KRAS, or EGFR alterations) by mass spectrometry (MS)-based quantitative proteomics and phosphoproteomics. We analyzed tumor regions of 82 formalin-fixed paraffin-embedded (FFPE) tissue sections with 6, 23, 31, and 22 samples from the EML4-ALK, EGFR, KRAS, and WT sample groups, respectively. A total of 1377 to 2189 proteins and 73 to 1781 phosphosites were quantified in these analyses. Based on the results, the samples clustered according to their genetic alteration type, and EGFR-mutated samples showed unique protein expression patterns. Membrane organization, vesicle organization, and vesicle-mediated transport Gene Ontology Biological Process (GOBP) terms were significantly downregulated in EGFR-mutated samples compared to the other sample groups. Changes in 36 proteins and 52 phosphosites were also identified as potentially specific to a given genetic alteration. Many of these proteins have previously been linked to EGFR or KRAS mutations [e.g., cathepsin L, stimulator of interferon genes protein (STING)], whereas several phosphoproteins are associated with RNA splicing [e.g., serine/arginine-rich splicing factor 1 (SRSF1), SRSF2, and SRSF7 proteins]. Kinase-substrate enrichment analysis indicated altered activities of 10 kinases, including mitogen-activated protein kinases (MAPKs) and cyclin-dependent kinases (CDKs). For example, CDK2 activity was elevated in EML4-ALK samples compared to the other sample groups. Our results could provide significant insights into further studies that could contribute to developing improved diagnostic and therapeutic strategies for LUAD.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6000,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/1878-0261.70091","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 0

Abstract

Genetic alterations in key oncogenes have been frequently identified in lung adenocarcinoma (LUAD), including genes encoding epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK). In this pilot study, we aimed to characterize the differences in enriched biological pathways and phosphorylation events between LUAD tumors harboring EGFR, KRAS, or echinoderm microtubule-associated protein-like 4 (EML4)-ALK oncogenic alterations and triple wild-type LUAD tumors (WT, without EML4-ALK, KRAS, or EGFR alterations) by mass spectrometry (MS)-based quantitative proteomics and phosphoproteomics. We analyzed tumor regions of 82 formalin-fixed paraffin-embedded (FFPE) tissue sections with 6, 23, 31, and 22 samples from the EML4-ALK, EGFR, KRAS, and WT sample groups, respectively. A total of 1377 to 2189 proteins and 73 to 1781 phosphosites were quantified in these analyses. Based on the results, the samples clustered according to their genetic alteration type, and EGFR-mutated samples showed unique protein expression patterns. Membrane organization, vesicle organization, and vesicle-mediated transport Gene Ontology Biological Process (GOBP) terms were significantly downregulated in EGFR-mutated samples compared to the other sample groups. Changes in 36 proteins and 52 phosphosites were also identified as potentially specific to a given genetic alteration. Many of these proteins have previously been linked to EGFR or KRAS mutations [e.g., cathepsin L, stimulator of interferon genes protein (STING)], whereas several phosphoproteins are associated with RNA splicing [e.g., serine/arginine-rich splicing factor 1 (SRSF1), SRSF2, and SRSF7 proteins]. Kinase-substrate enrichment analysis indicated altered activities of 10 kinases, including mitogen-activated protein kinases (MAPKs) and cyclin-dependent kinases (CDKs). For example, CDK2 activity was elevated in EML4-ALK samples compared to the other sample groups. Our results could provide significant insights into further studies that could contribute to developing improved diagnostic and therapeutic strategies for LUAD.

揭示具有或不具有ALK、EGFR和KRAS基因改变的肺腺癌中独特的蛋白质和磷酸化特征。
肺腺癌(LUAD)中经常发现关键癌基因的遗传改变,包括编码表皮生长因子受体(EGFR)、克尔斯滕大鼠肉瘤病毒癌基因同源物(KRAS)和间变性淋巴瘤激酶(ALK)的基因。在这项初步研究中,我们旨在通过基于质谱(MS)的定量蛋白质组学和磷酸化蛋白质组学来表征具有EGFR、KRAS或棘皮微管相关蛋白样4 (EML4)-ALK致癌改变的LUAD肿瘤和三种野生型LUAD肿瘤(WT,没有EML4-ALK、KRAS或EGFR改变)之间富集的生物学途径和磷酸化事件的差异。我们分析了82个福尔马林固定石蜡包埋(FFPE)组织切片的肿瘤区域,分别来自EML4-ALK、EGFR、KRAS和WT样品组的6、23、31和22个样本。在这些分析中,共定量了1377 ~ 2189个蛋白和73 ~ 1781个磷酸化位点。根据结果,样品根据其基因改变类型聚类,egfr突变样品显示出独特的蛋白质表达模式。与其他样品组相比,egfr突变样品中的膜组织、囊泡组织和囊泡介导的运输基因本体生物过程(GOBP)术语显著下调。36种蛋白质和52种磷位点的变化也被确定为特定于特定基因改变的潜在变化。许多这些蛋白先前与EGFR或KRAS突变相关[例如,组织蛋白酶L,干扰素基因刺激蛋白(STING)],而一些磷酸化蛋白与RNA剪接相关[例如,丝氨酸/精氨酸丰富剪接因子1 (SRSF1), SRSF2和SRSF7蛋白]。激酶底物富集分析显示10种激酶的活性改变,包括丝裂原活化蛋白激酶(MAPKs)和细胞周期蛋白依赖性激酶(CDKs)。例如,与其他样品组相比,EML4-ALK样品中的CDK2活性升高。我们的结果可以为进一步的研究提供重要的见解,有助于开发改进的LUAD诊断和治疗策略。
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 求助全文
来源期刊
Molecular Oncology
Molecular Oncology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
11.80
自引率
1.50%
发文量
203
审稿时长
10 weeks
期刊介绍: Molecular Oncology highlights new discoveries, approaches, and technical developments, in basic, clinical and discovery-driven translational cancer research. It publishes research articles, reviews (by invitation only), and timely science policy articles. The journal is now fully Open Access with all articles published over the past 10 years freely available.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信