«上一篇/Previous Article|本期目录/Table of Contents|下一篇/Next Article»

《中华肺部疾病杂志》[ISSN:1006-6977/CN:61-1281/TN]

卷:

期数:

2024年02期

页码:

195-200

栏目:

论著

出版日期:

2024-04-25

文章信息/Info

Title:

Transcriptomics-based exploration of the mechanism of acquired resistance to Osimertinib

作者:

张 剑; 卢从华; 李江华; 林采余; 吴 迪; 王治国; 聂乃夫; 何 勇; 李 力

400042 重庆,陆军(第三)军医大学陆军特色医学中心呼吸与危重症医学科

Author(s):

Zhang Jian;  Lu Conghua;  Li Jianghua;  Lin Caiyu;  Wu Di;  Wang Zhiguo;  Nie Naifu;  He Yong;  Li Li.

Department of Respiratory and Critical Care Medicine, Army characteristic Medical Center of PLA, Army Medical University, Chongqing 400042, China

关键词:

转录组测序;  奥希替尼;  支气管肺癌;  获得性耐药

Keywords:

Transcriptome sequencing;  Osimertinib;  Bronchogenic carcinoma;  Acquired drug resistance

分类号:

R734.2

DOI:

10.3877/cma.j.issn.1674-6902.2024.02.005

摘要:

目的 根据转录组测序技术分析介导肺癌奥希替尼耐药的信号通路,发现潜在干预靶点。方法 体外构建肺癌奥希替尼一线/二线治疗模式下配对的敏感/耐药细胞株,采用高通量测序技术检测耐药前后细胞转录本表达量并使用R-package CORNAS筛选差异表达基因,借助Venny在线工具分析两组配对细胞株差异表达基因的交集,运用DAVID Bioinformatics Resources数据库分别对两种耐药模式下共有差异基因和特有差异基因进行京都基因与基因组百科全书(kyoto Encyclopedia of Genes and Genomes, KEGG)信号通路和基因本体(gene ontology, GO)功能富集分析。采用STRING 12.0数据库分析关键通路富集基因相互作用关系及靶点分子,借助chiplot在线工具绘制分子相互作用网络图。结果 两组配对细胞株共有差异表达基因显著富集在Cell Cycle通路,一线治疗耐药特有差异基因富集在Cell Cycle和Ribosome biogenesis in eukaryotes通路,二线治疗耐药特有差异基因富集在MAPK signaling通路; GO富集分析发现共有差异表达基因参与cell division,分子功能是ATP binding,一、二线治疗耐药特有差异表达基因分别参与了rRNA processing和inflammatory response生物过程,主要分子功能分别是RNA binding和Protein binding; 共筛选出5种关键靶点分子,包括CCNB1(共有)、CDC25A 和NOP56(一线耐药特有)、JUN和MYC(二线耐药特有)。结论 奥希替尼一线或二线治疗模式下共同及特有的潜在获得性耐药机制,为克服奥希替尼耐药提供潜在的治疗靶点。

Abstract:

Objective To explore the signaling pathways mediating Osimertinib resistance in lung cancer based on transcriptome sequencing technology and to identify potential targets for intervention. Methods In vitro, we constructed paired sensitive/resistant lung cancer cell lines under the first/second line treatment modes of Osimertinib, detected the expression of cell transcripts before and after drug resistance by high-throughput sequencing and screened the differentially expressed genes by R-package CORNAS, analyzed the intersection of differentially expressed genes between the two groups of paired cell lines with the help of Venny online tool, and using the DAVID Bioinformatics Resources database to perform kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway and gene ontology(GO)function enrichment analysis on the common and unique differentially expressed genes in two drug-resistant modes, respectively. Finally, the STRING 12.0 database was used to analyze the key pathway enriched gene interactions and target molecules, and the molecular interaction network was mapped with the help of chiplot online tool. Results The shared differentially expressed genes of the two paired cell lines were significantly enriched in the Cell Cycle pathway, the first-line treatment resistance-specific differentially expressed genes were enriched in the Cell Cycle and Ribosome biogenesis in eukaryotes pathway, and the second-line treatment resistance-specific differentially expressed genes were enriched in the MAPK signaling pathway; GO enrichment analysis revealed that shared differentially expressed genes were involved in cell division, and their molecular function was ATP binding, while first- and second-line treatment resistance-specific differentially expressed genes were involved in rRNA processing and inflammatory response, and their main molecular functions were RNA binding and Protein binding, respectively; Five key target molecules were screened, including CCNB1(common), CDC25A and NOP56(first-line drug resistance-specific), JUN and MYC(second-line drug resistance-specific). Conclusions The study identified potential acquired resistance mechanisms common and specific to first-or second-line treatment modalities of Osimertinib, providing potential therapeutic targets for overcoming Osimertinib resistance.

参考文献/References:

1 徐天亮, 程干思, 吴亚平, 等. 奥希替尼联合安罗替尼二线治疗转移性NSCLC的疗效分析[J/CD]. 中华肺部疾病杂志(电子版), 2023, 16(4): 520-522.
2 Cheng Y, He Y, Li W, et al. Osimertinib versus comparator EGFR TKI as first-line treatment for EGFR-Mutated advanced NSCLC: FLAURA China, a randomized study[J]. Target Oncol, 2021, 16(2): 165-176.
3 Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer[J]. N Engl J Med, 2017, 376(7): 629-640.
4 Elkrief A, Makhnin A, Moses KA, et al. Brief report: Combination of osimertinib and dacomitinib to mitigate primary and acquired resistance in EGFR-Mutant lung adenocarcinomas[J]. Clin Cancer Res, 2023, 29(8): 1423-1428.
5 Chamorro DF, Cardona AF, Rodríguez J, et al. Genomic landscape of primary resistance to osimertinib among hispanic patients with EGFR-mutant non-small cell lung cancer(NSCLC): Results of an observational longitudinal cohort study[J]. Target Oncol, 2023, 18(3): 425-440.
6 Li X, Wang S, Li B, et al. BIM Deletion polymorphism confers resistance to osimertinib in EGFR T790M lung cancer: a case report and literature review[J]. Target Oncol, 2018, 13(4): 517-523.
7 Isobe K, Yoshizawa T, Sekiya M, et al. Quantification of BIM mRNA in circulating tumor cells of osimertinib-treated patients with EGFR mutation-positive lung cancer[J]. Respir Investig, 2021, 59(4): 535-544.
8 Kwon CS, Lin HM, Crossland V, et al. Non-small cell lung cancer with EGFR exon 20 insertion mutation: a systematic literature review and meta-analysis of patient outcomes[J]. Curr Med Res Opin, 2022, 38(8): 1341-1350.
9 Lazzari C, Gregorc V, Karachaliou N, et al. Mechanisms of resistance to osimertinib[J]. J Thorac Dis, 2020, 12(5): 2851-2858.
10 Ríos-Hoyo A, Moliner L, Arriola E. Acquired mechanisms of resistance to osimertinib-the next challenge[J]. Cancers(Basel), 2022, 14(8): 1931.
11 Oxnard GR, Hu Y, Mileham KF, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib[J]. JAMA Oncol, 2018, 4(11): 1527-1534.
12 Yang Z, Yang N, Ou Q, et al. Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients[J]. Clin Cancer Res, 2018, 24(13): 3097-3107.
13 Le X, Puri S, Negrao MV, et al. Landscape of EGFR-dependent and-independent resistance mechanisms to osimertinib and continuation therapy beyond progression in EGFR-mutant NSCLC[J]. Clin Cancer Res, 2018, 24(24): 6195-6203.
14 Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer[J]. Br J Cancer, 2019, 121(9): 725-737.
15 Mehlman C, Cadranel J, Rousseau-Bussac G, et al. Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study[J]. Lung Cancer, 2019, 137: 149-156.
16 Nie N, Li J, Zhang J, et al. First-Line Osimertinib in patients with EGFR-mutated non-small cell lung cancer: Effectiveness, resistance mechanisms, and prognosis of different subsequent treatments[J]. Clin Med Insights Oncol, 2022, 16: 11795549221134735.
17 Kim D, Pertea G, Trapnell C, et al. TopHat 2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions[J]. Genome Biol, 2013, 14(4): R36.
18 Marioni JC, Mason CE, Mane SM, et al. RNA-seq: an assessment of technical reproducibility and comparison with gene expression arrays[J]. Genome Res, 2008, 18(9): 1509-1517.
19 Zhao S, Zhang D, Liu S, et al. The roles of NOP56 in cancer and SCA36[J]. Pathol Oncol Res, 2023, 29: 1610884.
20 Hong H, Luo B, Qin Y, et al. RNA-seq and integrated network analysis reveals the hub genes and key pathway of paclitaxel inhibition on Adriamycin resistant diffuse large B cell lymphoma cells[J]. Bioengineered, 2022, 13(3): 7607-7621.
21 Tong X, Zhang R, Sun R, et al. Disclosing potential therapeutic targets associated with osimertinib resistance in the non-small cell lung cancer cell line H1975[J]. Anticancer Res, 2023, 43(12): 5459-5474.
22 Wang H, Chen X, He T, et al. Evidence for tissue-specific Jak/STAT target genes in Drosophila optic lobe development[J]. Genetics, 2013, 195(4): 1291-1306.
23 Yang F, Zhang S, Meng Q, et al. CXCR1 correlates to poor outcomes of EGFR-TKI against advanced non-small cell lung cancer by activating chemokine and JAK/STAT pathway[J]. Pulm Pharmacol Ther, 2021, 67: 102001.
24 Oster SK, Ho CS, Soucie EL, et al. The myc oncogene: Marvelousl Y Complex[J]. Adv Cancer Res, 2002, 84: 81-154.
25 Zhu L, Chen Z, Zang H, et al. Targeting c-Myc to overcome acquired resistance of EGFR mutant NSCLC cells to the third-generation EGFR tyrosine kinase inhibitor, osimertinib[J]. Cancer Res, 2021, 81(18): 4822-4834.
26 Lu W, Zhou Q, Chen Y. Impact of RNA degradation on next-generation sequencing transcriptome data[J]. Genomics, 2022, 114(4): 110429.
27 Zhang M, Wu J, Zhong W, et al. DNA-methylation-induced silencing of DIO3OS drives non-small cell lung cancer progression via activating hnRNPK-MYC-CDC25A axis[J]. Mol Ther Oncolytics, 2021, 23: 205-219.
28 Bao B, Yu X, Zheng W. MiR-139-5p targeting CCNB1 modulates proliferation, migration, invasion and cell cycle in lung adenocarcinoma[J]. Mol Biotechnol, 2022, 64(8): 852-860.

备注/Memo

备注/Memo:

基金项目: 国家自然科学基金资助项目(82272908) 通信作者: 李 力, Email: dpyyhxlili@tmmu.edu.cn

常用功能

更新日期/Last Update: 2024-04-20