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Published on: April 6, 2016
Molecular correlates of gefitinib responsiveness in human bladder cancer cells
Marissa Shrader1, Maria Simona Pino, Gordon Brown
1Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Unit 173, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Abstract:
We characterized the effects of the small molecule epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839, Iressa) on cell proliferation in a panel of 17 human bladder cancer cell lines. Gefitinib inhibited DNA synthesis in a concentration-dependent fashion in 6 of 17 lines. Growth inhibition was associated with p27(Kip1) accumulation and decreased cyclin-dependent kinase 2 activity. Gefitinib also inhibited baseline EGFR, AKT, and extracellular signal-regulated kinase (ERK) phosphorylation in the EGFR-dependent cells maintained in serum-free medium, whereas it had no effect on baseline EGFR or ERK phosphorylation in the EGFR-independent cells. Analyses of candidate markers of EGFR dependency revealed that the gefitinib-sensitive cells expressed higher surface EGFR levels than the gefitinib-resistant lines. Gefitinib-sensitive cells generally expressed higher levels of E-cadherin and lower levels of vimentin than the gefitinib-resistant cells, but these correlations were not perfect, suggesting that these markers of epithelial-mesenchymal transition cannot be used by themselves to prospectively predict EGFR-dependent growth. Together, our results show that bladder cancer cells are markedly heterogeneous with respect to their sensitivity to EGFR antagonists. Although surface EGFR levels and epithelial-mesenchymal transition status seem to roughly correlate with responsiveness, they cannot be used by themselves to identify bladder tumors that will be sensitive to EGFR-directed therapy. However, comparing levels of p27(Kip1) or DNA synthesis before and after gefitinib exposure does identify the drug-sensitive cells.
Insights
Gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, reduced DNA synthesis in some bladder cancer cells. While EGFR levels and epithelial-mesenchymal transition markers showed some correlation, p27Kip1 levels best identified sensitive cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bladder cancer exhibits heterogeneity in its response to targeted therapies.
- Epidermal growth factor receptor (EGFR) signaling plays a role in various cancers.
- Small molecule inhibitors targeting EGFR are a focus of cancer therapy development.
Purpose of the Study:
- To investigate the effects of gefitinib, an EGFR inhibitor, on human bladder cancer cell proliferation.
- To identify predictive markers for gefitinib sensitivity in bladder cancer.
- To understand the mechanisms underlying gefitinib's action in bladder cancer cells.
Main Methods:
- Screening of 17 human bladder cancer cell lines for sensitivity to gefitinib.
- Assessing DNA synthesis, p27Kip1 accumulation, and cyclin-dependent kinase 2 activity.
- Analyzing EGFR, AKT, and extracellular signal-regulated kinase (ERK) phosphorylation.
- Evaluating surface EGFR levels and epithelial-mesenchymal transition markers (E-cadherin, vimentin).
Main Results:
- Gefitinib inhibited DNA synthesis in 6 out of 17 bladder cancer cell lines in a dose-dependent manner.
- Inhibition was linked to increased p27Kip1 levels and reduced CDK2 activity.
- Sensitive cells showed higher surface EGFR and generally epithelial markers (E-cadherin), while resistant cells had lower EGFR and mesenchymal markers (vimentin).
- Epithelial-mesenchymal transition markers alone were not perfect predictors of gefitinib response.
Conclusions:
- Bladder cancer cells display significant heterogeneity in their response to EGFR inhibitors like gefitinib.
- Surface EGFR levels and epithelial-mesenchymal transition markers offer a rough correlation but are insufficient for predicting sensitivity.
- Measuring p27Kip1 levels or DNA synthesis before and after gefitinib treatment effectively identifies sensitive bladder cancer cells.
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