Epidermal growth factor receptor status and the response of bladder carcinoma cells to erlotinib.
OBJECTIVE
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.


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.
Jacobs
Micah A
MA
Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts 01805, USA.
Wotkowicz
Chad
C
Baumgart
Egbert D
ED
Neto
Brasil Silva
BS
Rieger-Christ
Kimberly M
KM
Bernier
Trisha
T
Cohen
Michael S
MS
Libertino
John A
JA
Summerhayes
Ian C
IC
D015153:Blotting, Western; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005091:Exons / Q000235:genetics; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D014410:Tumor Stem Cell Assay; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases