title: The epidermal growth factor receptor inhibitor gefitinib prevents the progression of pancreatic lesions to carcinoma in a conditional LSL-KrasG12D/+ transgenic mouse model.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy with a dismal prognosis. Developing novel strategies to prevent or delay pancreatic cancer is currently of intense interest. The chemopreventive efficacy of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, was evaluated against the progression of pancreatic intraepithelial neoplasms (PanIN) to PDAC in conditional LSL-Kras(G12D/+) transgenic mice. LSL-Kras(G12D/+) and p48(Cre/+) mice were bred, and offspring of activated Kras(G12D/+) were generated. Six-week-old male Kras(G12D/+) (20 per group) and C57BL/6 wild-type (12 per group) mice were fed (AIN-76A) diets containing 0, 100, and 200 ppm of gefitinib for 35 weeks. At termination, pancreases were evaluated histopathologically for PanINs and PDAC, and various biomarkers were measured by immunohistochemistry, immunofluorescence, immunoblotting, and/or reverse transcription-PCR. Dietary gefitinib at 100 and 200 ppm significantly suppressed PDAC incidence by 77% and 100%, respectively (P < 0.0001) when compared with control diet. Importantly, a significant inhibition of carcinoma and a dose-dependent suppression of PanINs [PanIN-1, 37-62% (P < 0.002); PanIN-2, 38-41 (P < 0.001); and PanIN-3, 7-34% (P < 0.0141)] were observed in mice treated with gefitinib. Furthermore, mice treated with 100 and 200 ppm of gefitinib exhibited 67.6% to 77.3% of the pancreas to be free from ductal lesions. Also, gefitinib reduced EGFR, proliferating cell nuclear antigen, cyclin D1, C(2)GNT, RhoA, β-catenin, p38, phospho-extracellular signal-regulated kinase, caveolin-1, and mucin and increased cyclin B1 in the pancreatic lesions/PDAC. In summary, these results show that gefitinib can prevent the progression of pancreatic cancer precursor lesions to PDAC in a preclinical model. The present study highlights the promise of chemoprevention and the potential usefulness of EGFR inhibitors in individuals at high risk for pancreatic cancer.
authors.affiliation: Center for Chemoprevention and Drug Development, Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.forename: Naveena B
authors.initials: NB
authors.lastname: Janakiram
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Venkateshwar
authors.initials: V
authors.lastname: Madka
authors.forename: Misty
authors.initials: M
authors.lastname: Ely
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.forename: Howard
authors.initials: H
authors.lastname: Crawford
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002278:Carcinoma in Situ / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005455:Fluorescent Antibody Technique; D000077156:Gefitinib; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib