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Published on: July 21, 2018
Lipid metabolic pathways as lung cancer therapeutic targets: a computational study
1Faculty of Information Science and Technology, Osaka Institute of Technology, Hirakata-City, Osaka, Japan. kyano@is.oit.ac.jp
Abstract:
Inhibitors of lipid metabolic pathways, particularly drugs targeting the mevalonate pathway, have been suggested to be valuable in enhancing the effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and these compounds may also be effective in patients with inherent or acquired resistance to EGFR-TKIs. The present study examined gene expression profiles in lung adenocarcinoma to characterize the interaction between growth factor signals and lipid metabolic pathways at the transcriptional level. Gene expression correlation analysis showed that genes involved in the mevalonate pathway and unsaturated fatty acid synthesis were negatively correlated with the expression of EGFR, MET and other growth factor receptor genes, as well as with the expression of genes involved in cell migration and adhesion. On the other hand, the expression of genes related to cell cycle progression, DNA repair and DNA replication were positively correlated with the metabolic pathway genes mentioned above, and a significant number of such genes had promoter domains for nuclear factor Y (NFY). Genes whose expression showed a positive correlation with NFY expression and mevalonate pathway genes were found to exhibit protein-protein interactions with several 'hub' genes, including BRCA1, that have been associated with both lung cancer and cell division. These results support the idea that inhibition of lipid metabolic pathways may be valuable as an alternative therapeutic option for the treatment of lung adenocarcinoma, and suggest that NFY is a possible molecular target for such efforts.
Insights
Inhibiting lipid metabolism pathways, like the mevalonate pathway, may enhance lung adenocarcinoma treatment. This approach could overcome resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs).
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are key in lung adenocarcinoma treatment.
- Resistance to EGFR-TKIs is a significant clinical challenge.
- Lipid metabolic pathways, especially the mevalonate pathway, are implicated in cancer progression and drug resistance.
Purpose of the Study:
- To investigate the transcriptional interplay between growth factor signaling and lipid metabolism in lung adenocarcinoma.
- To explore the potential of targeting lipid metabolic pathways as a therapeutic strategy for lung adenocarcinoma, including in cases of resistance to EGFR-TKIs.
Main Methods:
- Gene expression profiling of lung adenocarcinoma tissues.
- Correlation analysis to assess relationships between growth factor receptor genes and lipid metabolic pathway genes.
- Identification of transcription factor binding sites, specifically for nuclear factor Y (NFY).
- Protein-protein interaction analysis involving key genes.
Main Results:
- Genes in the mevalonate pathway and unsaturated fatty acid synthesis were negatively correlated with EGFR, MET, and other growth factor receptor genes.
- Positive correlations were observed between lipid metabolism genes and genes involved in cell cycle progression, DNA repair, and replication.
- A significant number of these correlated genes possess NFY binding sites.
- Genes positively correlated with NFY and mevalonate pathway genes interacted with cancer-associated hub genes like BRCA1.
Conclusions:
- Inhibition of lipid metabolic pathways presents a promising therapeutic avenue for lung adenocarcinoma.
- Targeting the mevalonate pathway may enhance EGFR-TKI efficacy and overcome resistance.
- Nuclear factor Y (NFY) emerges as a potential molecular target for therapeutic intervention in lung adenocarcinoma.
