Epidermal Growth Factor Receptor Inhibitor Gefitinib vents the Progression of Pancreatic Lesions to Carcinoma

wnloaded creatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy with a dismal osis. Developing novel strategies to prevent or delay pancreatic cancer is currently of intense intere chemopreventive efficacy of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, was ted against the progression of pancreatic intraepithelial neoplasms (PanIN) to PDAC in conditional ras transgenic mice. LSL-Kras and p48 mice were bred, and offspring of activated 2D/+ were generated. Six-week-old male Kras (20 per group) and C57BL/6 wild-type (12 per ) mice were fed (AIN-76A) diets containing 0, 100, and 200 ppm of gefitinib for 35 weeks. At terion, pancreases were evaluated histopathologically for PanINs and PDAC, and various biomarkers easured by immunohistochemistry, immunofluorescence, immunoblotting, and/or reverse tranon-PCR. Dietary gefitinib at 100 and 200 ppm significantly suppressed PDAC incidence by 77% 00%, respectively (P < 0.0001) when compared with control diet. Importantly, a significant inhiof carcinoma and a dose-dependent suppression of PanINs [PanIN-1, 37-62% (P < 0.002); PanIN41 (P < 0.001); and PanIN-3, 7-34% (P < 0.0141)] were observed in mice treated with gefitinib. rmore, mice treated with 100 and 200 ppm of gefitinib exhibited 67.6% to 77.3% of the pancreas free from ductal lesions. Also, gefitinib reduced EGFR, proliferating cell nuclear antigen, cyclin D1, T, RhoA, β-catenin, p38, phospho-extracellular signal–regulated kinase, caveolin-1, and mucin and sed cyclin B1 in the pancreatic lesions/PDAC. In summary, these results show that gefitinib can t the progression of pancreatic cancer precursor lesions to PDAC in a preclinical model. The present preven study highlights the promise of chemoprevention and the potential usefulness of EGFR inhibitors in individuals at high risk for pancreatic cancer. Cancer Prev Res; 3(11); 1417–26. ©2010 AACR.