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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and
Maria Villalba1,2,3, Esther Redin1,2, Francisco Exposito1,2,3
1IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Abstract:
Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4.
Insights
Researchers discovered a new synthetic lethal interaction between TMPRSS4 and DDR1 in non-small cell lung cancer (NSCLC). Targeting this vulnerability offers a promising new strategy for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) requires novel therapeutic targets.
- TMPRSS4 is a known promoter of NSCLC growth and a prognostic biomarker.
- Synthetic lethality presents a novel approach for targeting NSCLC.
Purpose of the Study:
- To identify novel therapeutic targets in NSCLC through synthetic lethality.
- To investigate the relationship between TMPRSS4 and DDR1 in NSCLC.
- To evaluate the therapeutic potential of targeting the TMPRSS4-DDR1 interaction.
Main Methods:
- Large-scale analysis of 5 public databases to identify gene co-expression.
- Analysis of DDR1 promoter methylation in NSCLC cohorts.
- Cell line experiments involving gene knockdown and drug treatments (dasatinib, cisplatin).
- In vivo studies using mouse models.
Main Results:
- Consistent co-expression of TMPRSS4 and DDR1 identified across databases.
- DDR1 promoter hypomethylation in NSCLC is linked to poorer disease-free survival.
- Combined knockdown of TMPRSS4 and DDR1 induced cell cycle arrest, apoptosis, and sensitization to cisplatin.
- Tumor regression observed in vivo in double knockdown models.
Conclusions:
- A synthetic lethal interaction between TMPRSS4 and DDR1 has been identified in NSCLC.
- This interaction represents a novel vulnerability and potential therapeutic target for NSCLC.
- Epigenetic regulation of DDR1 by hypomethylation is implicated in NSCLC progression.
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