Molecular correlates of gefitinib responsiveness in human bladder cancer cells

Marissa Shrader, Maria Simona Pino, Gordon Brown, Peter Black, Liana Adam, Menahse Bar-Eli, Colin P.N. Dinney, David J. McConkey

Research output: Contribution to journalArticlepeer-review

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 p27Kip1 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 p27Kip1 or DNA synthesis before and after gefitinib exposure does identify the drug-sensitive cells.

Original languageEnglish (US)
Pages (from-to)277-285
Number of pages9
JournalMolecular cancer therapeutics
Volume6
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Molecular correlates of gefitinib responsiveness in human bladder cancer cells'. Together they form a unique fingerprint.

Cite this