title: Molecular correlates of gefitinib responsiveness in human bladder cancer cells.
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.
authors.affiliation: Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Unit 173, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Shrader
authors.forename: Maria Simona
authors.initials: MS
authors.lastname: Pino
authors.forename: Gordon
authors.initials: G
authors.lastname: Brown
authors.forename: Peter
authors.initials: P
authors.lastname: Black
authors.forename: Liana
authors.initials: L
authors.lastname: Adam
authors.forename: Menahse
authors.initials: M
authors.lastname: Bar-Eli
authors.forename: Colin P N
authors.initials: CP
authors.lastname: Dinney
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects; D000077156:Gefitinib; D006801:Humans; D008648:Mesoderm / Q000187:drug effects; D051379:Mice; D011799:Quinazolines / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D004273:DNA, Neoplasm; D011799:Quinazolines; D042442:Vascular Endothelial Growth Factors; D066246:ErbB Receptors; D000077156:Gefitinib