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Published on: July 21, 2018
Targeting galactose metabolic reprogramming overcomes immunotherapy resistance in KRAS-mutant lung adenocarcinoma:
Long Qian1, Juan Zhao1, Mengtao Fan1
1Department of Cardiothoracic Surgery, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China.
Background:
KRAS-mutant lung adenocarcinoma (LUAD) is associated with aggressive phenotypes and therapy resistance, which highlights an urgent need to identify reliable biomarkers and therapeutic targets. This study aims to investigate the role of galactose metabolism (GM) reprogramming in shaping the tumor microenvironment (TME) and driving immunotherapy resistance in KRAS-mutant LUAD.
Methods:
Bulk-tissue transcriptomics data were collected from public cohorts such as Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Single-cell RNA-sequencing (scRNA-seq) data, mutational profiles, and advanced bioinformatic approaches were integrated to analyze the correlation between mutation status and metabolic heterogeneity in LUAD. Analytical methods included dimensionality reduction, differential expression, intercellular communication, trajectory inference, gene co-expression network analysis, molecular subtyping, and machine learning-based prognostic modeling. Animal experiment and flow cytometry were performed to validate KDM5A inhibitor (CPI-455) can sensitize KRAS-mutant LUAD cells to immunotherapy.
Results:
Single-cell analysis revealed reduced immune infiltration and upregulated GM in KRAS-mutant epithelial cells. Two GM-based molecular subtypes with distinct mutational profiles and immune patterns were identified. A prognostic model integrating GM-related genes demonstrated superior predictive performance. KDM5A was identified as a key predictor of ICB resistance. Targeting KDM5A can enhance the sensitivity to immunotherapy in KRAS-mutant LUAD.
Conclusion:
Our findings highlight the therapeutic potential of targeting galactose metabolism-related hub genes to sensitize KRAS-mutant LUAD to immunotherapy.
Insights
Targeting galactose metabolism in KRAS-mutant lung adenocarcinoma (LUAD) can overcome immunotherapy resistance. Reprogramming metabolic pathways and targeting KDM5A shows promise for enhancing treatment efficacy in LUAD patients.
Area of Science:
- Oncology
- Metabolic pathways
- Immunotherapy
Background:
- KRAS-mutant lung adenocarcinoma (LUAD) exhibits aggressive behavior and resistance to therapies.
- Identifying reliable biomarkers and therapeutic targets for KRAS-mutant LUAD is crucial.
- Galactose metabolism (GM) reprogramming may influence the tumor microenvironment (TME) and immunotherapy resistance.
Purpose of the Study:
- To investigate the role of GM reprogramming in KRAS-mutant LUAD.
- To explore the impact of GM on the TME and immunotherapy resistance.
- To identify potential therapeutic targets for KRAS-mutant LUAD.
Main Methods:
- Analysis of bulk-tissue transcriptomics data from public cohorts (GEO, TCGA).
- Integration of single-cell RNA-sequencing (scRNA-seq) data, mutational profiles, and bioinformatic approaches.
- Validation using animal experiments and flow cytometry to assess KDM5A inhibitor efficacy.
Main Results:
- Single-cell analysis showed reduced immune infiltration and increased GM in KRAS-mutant LUAD cells.
- Two GM-based molecular subtypes with distinct characteristics were identified.
- KDM5A was identified as a predictor of immunotherapy resistance, and its inhibition sensitized KRAS-mutant LUAD to immunotherapy.
Conclusions:
- Targeting GM-related genes holds therapeutic potential for KRAS-mutant LUAD.
- Modulating GM can sensitize KRAS-mutant LUAD to immunotherapy.
- KDM5A inhibition represents a promising strategy to enhance immunotherapy response in KRAS-mutant LUAD.
