Molecular correlates of gefitinib responsiveness in human bladder cancer cells.
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.
Shrader
Marissa
M
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Unit 173, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Pino
Maria Simona
MS
Brown
Gordon
G
Black
Peter
P
Adam
Liana
L
Bar-Eli
Menahse
M
Dinney
Colin P N
CP
McConkey
David J
DJ
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
D000970:Antineoplastic Agents; D015415:Biomarkers; D004273:DNA, Neoplasm; D011799:Quinazolines; D042442:Vascular Endothelial Growth Factors; D066246:ErbB Receptors; D000077156:Gefitinib