Identification of lapatinib sensitivity-related genes by integrative functional module analysis
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Qi-Hua Yuan1, Guodong Liu1, Qiuhui Hu2
1Department of Gastrointestinal Surgery, Yidu Central Hospital Affiliated to Weifang Medical University, Qingzhou 262500, China.
Background:
Globally, gastric carcinoma (GC) is one of the most commonly encountered malignancies and is the second highest contributor to cancer mortality. Lapatinib is a potent, orally-bioavailable small-molecule inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases, and is administered to treat GC. However, a large proportion of patients either develop resistance to or do not respond to lapatinib, often because the treatment activates alternative signaling pathways. It is, therefore, vital to identify the key pathways which mediate resistance to lapatinib treatment.
Methods:
The lapatinib sensitivity-related genes were extracted from the CellMiner database (version 2.2) using "NCI-60 Analysis Tools". The differentially expressed genes (DEGs) in gastric cancer were derived from The Cancer Genome Atlas (TCGA) database, the protein-protein interaction (PPI) network was derived from the Human Protein Reference Database (HPRD), and the Database for Annotation, Visualization and Integrated Discovery (DAVID) facilitated the functional analysis. The cell function was tested by CCK-8 cell viability assay, colony formation assay, acridine orange/ethidium bromide (AO/EB) staining, and Transwell assay.
Results:
The functional linkage networks of lapatinib sensitivity were constructed. Two modules were identified, and pathway analysis indicated that these modules were involved in several pathways, including the neuroactive ligand-receptor interaction network and the Rap1 signaling pathway. Finally, the breast cancer anti-estrogen resistance 1 (BCAR1) gene was selected for further study with lapatinib-resistant SUN216 cells (SUN216/LR). We found the expression of BCAR1 was upregulated in SUN216/LR cells compared to SUN216 cells. The IC50 of lapatinib in SUN216/LR cells was reduced upon BCAR1 knockdown, as measured by a CCK-8 assay. A clonogenic assay showed fewer SUN216/LR colonies with BCAR1 knockdown and lapatinib treatment.
Conclusions:
In brief, we efficiently identified those crucial modules highly related to lapatinib sensitivity in GC by using a topological network method. BCAR1 was identified as a potentially critical gene that plays a role in lapatinib sensitivity, and experiments confirmed that BCAR1 might contribute to lapatinib resistance in GC. These results provide further insight into the molecular basis of lapatinib sensitivity and may offer novel strategies for the future treatment of GC.
Insights
This study identifies breast cancer anti-estrogen resistance 1 (BCAR1) as a key gene contributing to lapatinib resistance in gastric cancer (GC). BCAR1 knockdown resensitizes GC cells to lapatinib, offering potential new treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastric carcinoma (GC) is a leading cause of cancer mortality worldwide.
- Lapatinib, a tyrosine kinase inhibitor, treats GC but faces resistance due to alternative signaling pathways.
- Identifying mechanisms of lapatinib resistance is crucial for effective GC treatment.
Purpose of the Study:
- To identify key pathways and genes mediating resistance to lapatinib in gastric cancer.
- To investigate the role of identified genes in lapatinib sensitivity and resistance.
Main Methods:
- Utilized CellMiner and TCGA databases for lapatinib sensitivity-related genes and differentially expressed genes in GC.
- Constructed protein-protein interaction networks using HPRD and performed functional analysis with DAVID.
- Assessed cell function and lapatinib resistance using CCK-8 assays, colony formation assays, and AO/EB staining.
Main Results:
- Functional linkage networks revealed modules involved in neuroactive ligand-receptor interaction and Rap1 signaling pathways.
- Breast cancer anti-estrogen resistance 1 (BCAR1) was upregulated in lapatinib-resistant GC cells (SUN216/LR).
- BCAR1 knockdown in SUN216/LR cells reduced lapatinib IC50 and colony formation, indicating resensitization to lapatinib.
Conclusions:
- Topological network analysis effectively identified critical modules related to lapatinib sensitivity in GC.
- BCAR1 plays a significant role in lapatinib sensitivity and may contribute to lapatinib resistance in GC.
- These findings offer insights into the molecular basis of lapatinib resistance and suggest novel therapeutic strategies for GC.
