Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China; Department of Healthcare Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Comput Biol Med. 2024 Mar;171:108078. doi: 10.1016/j.compbiomed.2024.108078. Epub 2024 Feb 5.
Immune checkpoint inhibitors (ICI) plus chemotherapy is the preferred first-line treatment for advanced driver-negative lung adenocarcinoma (LUAD). The DNA damage response (DDR) is the main mechanism underlying chemotherapy resistance, and EGLN3 is a key DDR component.
We conducted an analysis utilizing TCGA and GEO databases employing multiple labels-WGCNA, DEGs, and prognostic assessments. Using bulk RNA-seq and scRNA-seq data, we isolated EGLN3 as the single crucial DDR gene. Spatial transcriptome analysis revealed the spatial differential distribution of EGLN3. TIDE/IPS scores and pRRophetic/oncoPredict R packages were used to predict resistance to ICI and chemotherapy drugs, respectively.
EGLN3 was overexpressed in LUAD tissues (p < 0.001), with the high EGLN3 expression group exhibiting a poor prognosis (p = 0.00086, HR: 1.126 [1.039-1.22]). Spatial transcriptome analysis revealed EGLN3 overexpression in cancerous and hypoxic regions, positively correlating with DDR-related and TGF-β pathways. Drug response predictions indicated EGLN3's resistance to the common chemotherapy drugs, including cisplatin (p = 6.1e-14), docetaxel (p = 1.1e-07), and paclitaxel (p = 4.2e-07). Furthermore, on analyzing the resistance mechanism, we found that EGLN3 regulated DDR-related pathways and induced chemotherapy resistance. Additionally, EGLN3 influenced TGF-β signaling, Treg cells, and cancer-associated fibroblast cells, culminating in immunotherapy resistance. Moreover, validation using real-world data, such as GSE126044, GSE135222, and, IMvigor210, substantiated the response trends to immunotherapy and chemotherapy.
EGLN3 emerges as a potential biomarker predicting lower response to both immunotherapy and chemotherapy, suggesting its promise as a therapeutic target in advanced LUAD.
免疫检查点抑制剂（ICI）联合化疗是晚期驱动基因阴性肺腺癌（LUAD）的首选一线治疗方法。DNA 损伤反应（DDR）是化疗耐药的主要机制，EGLN3 是 DDR 的关键组成部分。
我们使用 TCGA 和 GEO 数据库进行了多标签-WGCNA、DEGs 和预后评估的分析。使用批量 RNA-seq 和 scRNA-seq 数据，我们分离出 EGLN3 作为单个关键 DDR 基因。空间转录组分析揭示了 EGLN3 的空间差异分布。TIDE/IPS 评分和 pRRophetic/oncoPredict R 包分别用于预测对 ICI 和化疗药物的耐药性。
EGLN3 在 LUAD 组织中高表达（p<0.001），高 EGLN3 表达组预后不良（p=0.00086，HR：1.126[1.039-1.22]）。空间转录组分析显示 EGLN3 在癌性和缺氧区域高表达，与 DDR 相关和 TGF-β 途径呈正相关。药物反应预测表明 EGLN3 对常见化疗药物如顺铂（p=6.1e-14）、多西他赛（p=1.1e-07）和紫杉醇（p=4.2e-07）耐药。此外，通过分析耐药机制，我们发现 EGLN3 调节 DDR 相关途径并诱导化疗耐药。此外，EGLN3 影响 TGF-β 信号、Treg 细胞和癌症相关成纤维细胞，导致免疫治疗耐药。此外，使用真实世界数据（如 GSE126044、GSE135222 和 IMvigor210）进行验证，证实了对免疫治疗和化疗的反应趋势。
EGLN3 是预测免疫治疗和化疗反应较低的潜在生物标志物，表明其有望成为晚期 LUAD 的治疗靶点。
