Abstract 1563: Role of EGFR during the transition of inflammation to dysplasia in a colitis-associated colon cancer model

Abstract

Abstract Background: The underlying mechanisms in ulcerative colitis-associated dysplasia are poorly understood. Neurokinin-1 receptors (NK-1R) have been shown to be involved in chronic colonic inflammation, and we have demonstrated their over-expression in patients with dysplasia. The NK-1R has been found to crosstalk with the epidermal growth factor receptor (EGFR). EGFR is related to the development of some cancers including colorectal cancer. Erlotinib, a potent inhibitor of the EGFR tyrosine kinase, has been shown to inhibit the intracellular EGFR signaling pathway and to block non-small cell lung cancer and pancreatic tumor growth; however its role in the genesis of dysplasia is unknown. Aim: The aim of this study was to investigate the role of EGFR in a novel model of colitis-associated dysplasia using a small molecule inhibitor, Erlotinib. Methods: Sprague Dawley rats received trinitrobenzene sulfonic acid (TNBS; 30 mg in 50% ethanol, ic.), followed six weeks later by reactivation with TNBS (5 mg/kg, iv.) for three days. To induce colitis-associated dysplasia, the rats then received TNBS (iv.) twice a week for ten weeks. One group received the Erlotinib (10 mg/kg, ip.) for one week before the start of the reactivation of the colitis and two weeks after (21 days); the rest received the vehicle. After sacrifice, the colons were removed and analyzed for damage and expression of NK-1R, Cox-2, EGFR, and the downstream signaling components. Results: Animals receiving Erlotinib had no significant difference in macroscopic or microscopic damage from controls. Pathological analysis however revealed a decrease of the incidence of dysplasia in animals treated with Erlotinib when compared with the vehicle-treated animals. This decrease was most evident in both the mid and the distal colon (15% vs. 53% and 20% vs. 61%). Colonic tissues from Erlotinib-treated animals also had decreased expression of NK-1R, Cox-2, pErk ½, and Akt compared to the vehicle-treated group. Conclusion: Our results suggest that Erlotinib can delay the development of colitis associated dysplasia, suggesting a potential therapeutic use for Erlotinib in patients with long-standing colitis. Supported in part by 1U56 CA126379-01 and 1F31 GM078951. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1563.