Abstract B84: EGFR activation by the ADAM17 sheddase is required for Kras-induced pancreatic tumorigenesis.

Abstract

Nearly 45% of early PanIN lesions and 90% of pancreatic ductal adenocarcinoma (PDA) harbor a Kras mutation which inhibits Kras9 intrinsic GTP-ase function, resulting in a constitutively active Kras. The canonical Ras-Raf-Erk pathway suggests that constitutively active Kras would also result in constant Erk activation, independent of upstream components. In this study we demonstrate that genetic ablation of either EGFR or ADAM17, the primary EGFR ligand sheddase, effectively prevents tumorigenesis in the LSL-Kras G12D/+ ; Ptf1a Cre/+ (KC) mouse model of pancreatic tumorigenesis. Both mice are also protected from cerulein-induced chronic pancreatitis. Surprisingly, both knockouts fail to show robust activation of ERK, even with the expression of oncogenic Kras. This observation can be reproduced in human pancreatic cancer cell lines harboring a mutant Kras, where inhibition of EGFR with erlotinib resulted in a significant decrease in Erk activity. Conversely, stimulation of EGFR by either addition of exogenous TGF-α or stimulation of ADAM 17 with the phorbol 12-myristate 13-acetate (PMA) resulted in an increase in Erk activity. These data demonstrate a clear link between EGFR signaling and Erk activity despite of the presence of a mutant Kras. That EGFR signaling is also required for the chronic pancreatitis phenotype suggests EGFR inhibition could be a potential method of preventative therapy for patients at risk of developing pancreatitis or cancer derived from it. Citation Format: Christopher J. Halbrook, Kenneth K. Takeuchi, Christine M. Ardito, Barbara M. Gruener, Jens T. Siveke, Howard C. Crawford. EGFR activation by the ADAM17 sheddase is required for Kras-induced pancreatic tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B84.