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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Identification of the key DNA damage response genes for predicting immunotherapy and chemotherapy efficacy in lung
Shijie Sun1, Kai Wang2, Deyu Guo3
1Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Background:
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.
Method:
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.
Results:
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.
Conclusions:
EGLN3 emerges as a potential biomarker predicting lower response to both immunotherapy and chemotherapy, suggesting its promise as a therapeutic target in advanced LUAD.
Insights
EGLN3 overexpression in lung adenocarcinoma predicts poor response to chemotherapy and immunotherapy. This key DNA damage response gene may be a therapeutic target for advanced disease.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Immune checkpoint inhibitors (ICI) plus chemotherapy is standard for advanced driver-negative lung adenocarcinoma (LUAD).
- DNA damage response (DDR) pathways are implicated in chemotherapy resistance.
- EGLN3 is identified as a key component within DDR pathways.
Purpose of the Study:
- To investigate the role of EGLN3 in LUAD treatment resistance.
- To analyze EGLN3 expression and its correlation with prognosis and therapeutic response.
- To explore EGLN3's potential as a predictive biomarker and therapeutic target.
Main Methods:
- Utilized TCGA and GEO databases for WGCNA, differential gene expression, and prognostic analyses.
- Employed bulk and single-cell RNA sequencing to identify EGLN3.
- Performed spatial transcriptome analysis and utilized TIDE/IPS and pRRophetic/oncoPredict packages for drug response prediction.
Main Results:
- EGLN3 was significantly overexpressed in LUAD tissues, correlating with poor prognosis.
- Spatial analysis showed EGLN3 overexpression in cancerous and hypoxic regions, linked to DDR and TGF-β pathways.
- EGLN3 predicted resistance to common chemotherapies (cisplatin, docetaxel, paclitaxel) and immunotherapy, influencing Treg and cancer-associated fibroblast cells.
Conclusions:
- EGLN3 is a potential biomarker for predicting reduced response to both chemotherapy and immunotherapy in advanced LUAD.
- EGLN3's role in regulating DDR and influencing immune microenvironment suggests it as a promising therapeutic target.
