Anti-Ras inhibitors currently under phase III clinical evaluation for cancer treatment have utilized two distinct approaches. First, farnesyltransferase inhibitors (FTIs) that block Ras C-terminal CAAX tetrapeptidesignaled famesylation and membrane association have been developed. However, while effective against HRas, FTIs are not effective inhibitors of K-Ras or of N-Ras, the isoforms most commonly mutated in human cancers. Therefore, inhibitors of the two other CAAX-signaled posttranslational modifications, catalyzed by Rce1and Icmt respectively, are now being evaluated as approaches to anti-Ras treatment that will be effective against all Ras isoforms. However, the importance of these two modifications for Ras-mediated oncogenesis in human tumor cells has not been evaluated. Furthermore, although these two modifications are presumably also important for the function of other Ras and Rho family GTPases that terminate in CAAX motifs, how inhibition of Rce1 and Icmt will affect the function of non-Ras targets has not been addressed. Second, inhibitors of Raf and MEK protein kinases have been evaluated in the clinic as approaches to block Ras-mediated activation of the ERK mitogen-activated protein kinase signaling cascade. However, recent evidence that Ras utilizes multiple Raf-independent pathways to cause transformation complicates the issue of how effective inhibitors of the Raf>MEK>ERK cascade will be for blocking oncogenic Ras in human cancer cells. In particular, studies in cell culture or mouse models provide evidence that the RalGEF>Ral and Tiam1>Rac effecter pathways may be critical pathways for Ras-mediated oncogenesis. Conversely, recent observations that mutationally activated forms of B-Raf and Ras occur in a nonoverlapping frequency in certain human cancers (e.g., melanomas and colorectal carcinomas) argue that Raf activation alone is sufficient for Ras-mediated oncogenesis. Thus, the issue of the importance of the Raf, RalGEF and Tiaml1 effectors in Ras transformation of human cells remains complicated and unresolved. We propose four specific aims to critically evaluate [1] the importance of Reel and Icmt as targets for anti-Ras treatment, and the importance of the [2] Raf>ERK [3] RalGEF>Ral, and [4] Tiam1>Rac effector pathways for oncogenic Kras transformation of pancreatic epithelial cells and promotion of pancreatic carcinoma growth.
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