EGF receptor is required for KRAS-induced pancreatic tumorigenesis.

Ardito CM, Grüner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, Pal D, Briel T, Herner A, Trajkovic-Arsic M, Sipos B, Liou GY, Storz P, Murray NR, Threadgill DW, Sibilia M, Washington MK, Wilson CL, Schmid RM, Raines EW, Crawford HC, Siveke JT
Cancer Cell. 2012 22 (3): 304-17

PMID: 22975374 · PMCID: PMC3443395 · DOI:10.1016/j.ccr.2012.07.024

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

MeSH Terms (16)

ADAM17 Protein ADAM Proteins Animals Carcinoma, Pancreatic Ductal Cell Line, Tumor Cell Transformation, Neoplastic Epithelial Cells ErbB Receptors Extracellular Signal-Regulated MAP Kinases Genes, ras Humans Mice Mice, Transgenic Pancreas Pancreatic Neoplasms Proto-Oncogene Proteins p21(ras)

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