Iressa is a selective inhibitor of the epidermal growth factor receptor\#8217;s (EGFR) tyrosine kinase domain. Iressa inhibits EGFR tyrosine kinase by binding to the EGFR adenosine triphosphate (ATP)-binding site, thereby inhibiting the ability of EGFR to phosphorylate and activate the Ras signal transduction cascade. EGFr inhibitors have potential in the treatment of various cancers, including breast and bladder cancers. The purpose of these research studies is to examine specific signal transduction endpoints to identify potential biomarkers and mechanisms of action of Iressa. For this work, Iressa sensitive (SK-Br-3) and resistant (MDA-MB-468) human breast cancer cells and Iressa sensitive (UM-UC5) and resistant (UM-UC14) human bladder cancer cells were utilized. Different concentrations (0.1, 1, 2.5, 5 µM) of Iressa were used for cell treatments. Breast Cancer. Iressa treatment dose-dependently decreased EGFR phosphorylation (Tyr992, Tyr1068, Tyr1110, Tyr1173) in Iressa-sensitive SK-Br-3 breast cancer cells, but had relatively less effect on EGFR phosphorylation at these same sites in Iressa-resistant MDA-MB-468 cells. Notably, Iressa caused G1 phase arrest in SK-Br-3 cells, but not in MDA-MB-468 cells. Iressa caused a dose-dependent decrease in phosphorylation of Akt (Ser473) in SK-Br-3 cells, but had no effect on Akt phosphorylation in MDA-MB-468 cells. Bladder Cancer. ERKs phosphorylation (Thr202/Tyr204) was decreased in UM-UC5 cells, but not in UM-UC14 cells after 24 h treatment with Iressa. Iressa also caused a strong G1 phase arrest in Iressa-sensitive UM-UC5 bladder cancer cells but had little effect on Iressa-resistant UM-UC1 cells. This corresponded with an increase in total p53 protein and phosphorylated p53 (Ser15) in UM-UC5 cells that was not observed in UM-UC14 cells at 24 h. Overall, the data suggest that Iressa resistance might be associated with differential effects on cell cycle regulation mediated by p53. Limited decreases in Akt activation and phosphorylation also appear to be associated with resistance of breast and bladder cancer cells to Iressa treatment.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3901.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO