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Epidermal growth factor receptor status and the response of bladder carcinoma cells to erlotinib
Micah A Jacobs1, Chad Wotkowicz, Egbert D Baumgart
1Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts 01805, USA.
Purpose:
We established the frequency of mutation of the epidermal growth factor receptor in bladder cancer and determined whether the activation status of epidermal growth factor receptor confers sensitivity to erlotinib.
Materials And Methods:
The identification of mutations in the kinase domain (exons 18-21) of epidermal growth factor receptor was performed using single strand conformation polymorphism. The action of erlotinib was established within a bladder carcinoma cell panel using clonogenic assays and Western blot analysis.
Results:
In 112 invasive bladder tumors a total of 6 mutations in 4 patients (3.6%) were identified in exon 21. Erlotinib demonstrated concentration dependent inhibition of growth where three cell lines showed high and 2 showed low sensitivity to the drug. Erlotinib inhibited activation of epidermal growth factor receptor, mitogen activated protein kinase, Akt and STAT3. However, the activation status of Akt was maintained in cell lines that were insensitive to the inhibitory action of erlotinib and were characterized as having undergone epithelial-to-mesenchymal transition.
Conclusions:
Although mutations in the coding region of epidermal growth factor receptor are rare in invasive bladder tumors, differential sensitivity to erlotinib was recorded within a panel of cell lines. Maintenance of the phosphorylation status of Akt in the presence of erlotinib along with epithelial-to-mesenchymal transition correlates with insensitivity to growth inhibition in bladder carcinoma cell lines. Even in the absence of epidermal growth factor receptor mutations erlotinib shows potential as a therapeutic agent for the treatment of bladder cancer.
Insights
Epidermal growth factor receptor mutations are rare in bladder cancer, but erlotinib shows therapeutic potential. Insensitivity to erlotinib correlates with epithelial-to-mesenchymal transition and sustained Akt activation.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) plays a role in various cancers.
- Targeted therapies are emerging for bladder cancer treatment.
Purpose of the Study:
- To determine the frequency of EGFR mutations in bladder cancer.
- To assess the sensitivity of bladder cancer cell lines to erlotinib.
- To investigate the correlation between EGFR activation status and erlotinib sensitivity.
Main Methods:
- EGFR mutations in exons 18-21 were identified using single-strand conformation polymorphism.
- Erlotinib's efficacy was evaluated in bladder cancer cell lines via clonogenic assays and Western blot.
- Activation of signaling pathways (EGFR, MAPK, Akt, STAT3) was assessed.
Main Results:
- Only 3.6% of invasive bladder tumors (4/112) harbored EGFR mutations in exon 21.
- Erlotinib exhibited concentration-dependent growth inhibition, with varying sensitivity across cell lines.
- Erlotinib inhibited EGFR, MAPK, Akt, and STAT3 activation.
- Insensitive cell lines maintained Akt phosphorylation and showed signs of epithelial-to-mesenchymal transition (EMT).
Conclusions:
- EGFR mutations are infrequent in invasive bladder cancer.
- Differential sensitivity to erlotinib was observed in bladder cancer cell lines.
- Sustained Akt phosphorylation and EMT are associated with erlotinib insensitivity.
- Erlotinib may hold therapeutic promise for bladder cancer, even without EGFR mutations.
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