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EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis

2012; Cell Press; Volume: 22; Issue: 3 Linguagem: Inglês

10.1016/j.ccr.2012.07.024

1878-3686

Christine M. Ardito, Barbara M. Grüner, Kenneth K. Takeuchi, Clara Lubeseder–Martellato, Nicole Teichmann, Paweł K. Mazur, Kathleen E. DelGiorno, Eileen S. Carpenter, Christopher J. Halbrook, Jason C. Hall, Debjani Pal, Thomas von Briel, Alexander Herner, Marija Trajkovic‐Arsic, Bence Sipos, Geou‐Yarh Liou, Peter Störz, Nicole R. Murray, David W. Threadgill, Maria Sibilia, M. Kay Washington, Carole L. Wilson, R Schmid, Elaine W. Raines, Howard C. Crawford, Jens T. Siveke,

Pancreatic function and diabetes

Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.