Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression

Activating mutations within the K-ras gene have been found in up to 90% of pancreatic carcinomas. Although multiple Ras effector pathways have been id entified, the Raf protein kinases which are upstream regulators of the mito gen-activated protein kinases (MAPK/Erk) are believed to be the primary mit ogenic effecters. Constitutive upregulation of this pathway by oncogenic ra s is thought to promote cellular transformation. To explore the biological effects of mutated K-ras, we analyzed the Ras signaling pathway in a panel of cell lines derived from human pancreatic carcinomas. We found that despi te high levels of Ras-GTP in each cell line expressing mutant K-ras, elevat ed levels of active Erk1 and Erk2 were not detectable under conditions of e xponential growth or serum-starvation. Depending upon the cell line, the bl ock in Erk signaling was observed to occur at either the level of Raf or Er k. Increased levels of active Erk1 and Erk2 were detected in only 2 out of 10 normal tissue-matched primary pancreatic tumors with mutated K-ras. Our results suggest that Erk signaling is not aberrantly upregulated in pancrea tic cancers containing oncogenic K-ras mutations. The lack of Erk activatio n observed in both cell lines and primary tumor tissue suggests that consti tutive Erk activation may not be required for tumor maintenance or progress ion in K-ras transformed pancreatic cells. We hypothesize that other Ras-de pendent signaling pathways or an unidentified Raf/Mek-dependent pathway may be important for carcinogenesis in the pancreas. These findings may have i mportant implications for drug treatment strategies which currently target the MAP kinase branch of the Ras signaling pathway.