The MAP-kinase interacting kinases (Mnks) as targets in cancer

Abstract

The Mnks appear to play an important role in tumour development, but are not essential for normal cell growth and development. This makes them attractive targets for designing anti-cancer treatments. The Mnks are directly downstream of the RAS-RAF-MEK-ERK pathway, a pathway that is frequently overactive in cancer cells. The Mnks bind to eIF4G, which is part of the translation initiation complex, and are the only kinases known to phosphorylate the 5’ mRNA cap-binding protein eIF4E. Despite numerous studies linking this phosphorylation event to cancer, its precise role in cancer remains unclear. The lack of progress in developing our understanding of the role the Mnks is largely down to the absence of a selective and potent Mnk inhibitor. Presented here are the results of experiments carried out using a novel Mnk inhibitor, Mnk-I1. These results are also backed up with the results of experiments using cells – Mouse Embryonic Fibroblasts (MEFs) - that have had the Mnks genetically knocked out. What the results show, is that Mnk kinase activity appears to play a key role in cancer cell migration. The mechanism appears to involve an important role for Mnk kinase activity in the translation of vimentin mRNA into protein and in preventing the degradation of the vimentin protein: an established marker of cells that have undergone Epithelial-Mesenchymal Transition (EMT) and become motile. The results presented in the last chapter focus on whether the Mnks might be suitable targets for overcoming acquired resistance to the MEK inhibitor AZD6244. In the context of a BRAF600E amplification, Mnk-I1 appeared to have a small antiproliferative effect in one cancer cell line tested; however, there was no effect on the proliferation of a cancer cell line with a KRAS13D amplification. Included in this set of data is an interesting effect of Mnk-I1 on increasing P-Mnk1 levels.

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