TKI resistance related genes in LUAD predict patient prognosis and tumor immune microenvironment with LHX2 as a hub gene
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Published on: October 11, 2019
Ruohan Huang1, Qi Liang1, Hongya Wang2
1Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
Background:
Non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma (LUAD), is a leading cause of cancer-related mortality. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), improves survival, but acquired resistance remains a major clinical challenge.
Methods:
Transcriptomic profiles of osimertinib-sensitive and -resistant EGFR-mutant cell lines were analyzed to identify resistance mechanisms. Resistance-associated genes were used to develop a Cox proportional hazards (CoxPH) prognostic model based on The Cancer Genome Atlas (TCGA) data. Immune context and tumor mutational burden (TMB) were compared between risk groups. Core gene expression was validated by reverse transcription quantitative polymerase chain reaction (RT‒qPCR). Functional experiments including Cell Counting Kit-8 (CCK8) and methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays were performed to evaluate the impact of core gene on the proliferative capacities of EGFR-TKI resistance cells.
Results:
Resistant cells showed gene expression alterations enriched in proliferation (e.g., Wnt) and cell cycle pathways. An 18-gene signature strongly predicted overall survival (concordance index [C-index] = 0.74). High-risk patients exhibited more immunosuppressive microenvironments and higher TMB. Nine genes (GLI2, LHX2, PITX3, MSX1, ANO1, MUC5B, BEST4, SLC46A3, ECEL1P2) were independent prognostic factors, and LHX2 occupied a central position. LHX2 was upregulated in resistant cells, and its knockdown restored osimertinib sensitivity.
Conclusion:
This study reveals novel genes and mechanisms in osimertinib resistance. The prognostic model stratifies LUAD patients effectively, and LHX2 represents a promising therapeutic target for reversing resistance.
Insights
Acquired resistance to osimertinib in lung adenocarcinoma (LUAD) involves gene expression changes. A novel prognostic model identifies high-risk patients and highlights LHX2 as a potential therapeutic target to overcome resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Lung adenocarcinoma (LUAD) is a major cause of cancer mortality.
- Osimertinib (EGFR-TKI) improves survival but acquired resistance is a challenge.
Purpose of the Study:
- Identify mechanisms of osimertinib resistance in EGFR-mutant LUAD.
- Develop a prognostic model for patient stratification.
- Investigate therapeutic targets for overcoming resistance.
Main Methods:
- Transcriptomic analysis of resistant cell lines.
- Development of a Cox proportional hazards (CoxPH) prognostic model using TCGA data.
- Validation of core gene expression and functional assays.
Main Results:
- Resistant cells exhibit altered proliferation and cell cycle pathways.
- An 18-gene signature effectively predicts overall survival (C-index=0.74).
- LHX2 identified as a key gene upregulated in resistance, its knockdown restores sensitivity.
Conclusions:
- Novel genes and mechanisms driving osimertinib resistance identified.
- Prognostic model effectively stratifies LUAD patients.
- LHX2 is a promising therapeutic target for reversing osimertinib resistance.
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