AZD6244 - Regulates The Downstream Kinases To BRAF And RAS

By [http://ezinearticles.com/?expert=Kate_Rabia]Kate Rabia
INTRODUCTION
Most of the human tumors are related with the up regulation of the MAPK pathway. This pathway gets activated as a response to various extracellular ligands, overexpression of few genes, mutations in genes belonging to BRAF and RAS family. The proteins encoded by BRAF and RAS genes regulate a common effector pathway. MEK1/2 are dual specific kinases which phosphorylate the ERK1/2, at their tyrosine and threonine residues and they later on modulate a number cellular responses. AZD6244 is a selective inhibitor of MEK1/2 and is presently undergoing phase II clinical trials. It has been found to be cytotoxic in various kinds of tumors.
STRUCTURE AND MECHANISM OF ACTION OF AZD6244
AZD6244 is an uncompetitive inhibitor of MEK1/2. It does not compete with ATP for its binding site. MEK1/2 are the downstream targets to BRAF and RAS. AZD6244 was found to be effective both under in vitro and in vivo conditions. The mechanism behind its action under in vivo conditions is cleavage of caspase-3, which effects the proliferation of cells and the cell viability. These results suggest that AZD6244 induces apoptosis and differentiation of tumor cells. It also enhanced the cytotoxic effects of other inhibitors like irinotecan and docetaxel. It showed proapoptotic action in Calu-6 and Colo-205, which were two xenograft models. When AZD6244 was tested in SW-620 model, it was found to be antiproliferative and induced cellular differentiation.
AZD6244: EFFECT ON TRANSCRIPTIONAL PATHWAY SIGNATURES
Diverse lineage of tumor cells were tested with AZD6244 and it was found that there is no perfect correlation between the mutation and phosphorylation of RAS, BRAF/MEK or PI3K activity. 18-gene signatures were identified to show differential expression and this was found to be present exclusively in resistant cells. This action was correlated to the mutational pathway activity. In case of cells which show an activation of MEK but are resistant to AZD6244, 13-gene signatures were identified. These results suggest that there is a complementary signaling pathway which starts from RAS effectors and is away from PI3K pathway. Different signatures were responsible for the functional activation of MEK and/or sensitivity to AZD6244, in different kinds of cancers. Hence there signatures helped in the study of the physiological role of MEK.
AZD6244: EFFECT ON BRAF GENE
At least 15% of cancers have been related to the mutations in RAS gene. 66% of cancers have been related with the mutations in BRAF (somatic missense) gene. The mutations within the RAF gene are in the kinase domain and are associated with the substitution of valine with glutamic acid at 599th position. This single substitution is responsible for the cancerous growth. At least 3 RAF genes have been identified which code for ser/thr kinases present in the cytoplasm. These kinases are modulated by the binding of the RAS. The inhibitors which can control the mutations in the BRAF gene can effectively put a check on the cancerous growth.
CONCLUSION
Cells which get mutated in BRAF gene become selectively sensitive to the MEK inhibition as this mutation is associated with suppressed expression of cyclin D1 protein. Being a selective inhibitor to MEK1/2, AZD6244 can effectively control the BRAF mutations. However this inhibitor can control the RAS mutation induced cancers partially. In a nut shell AZD6244 controls the kinases lying downstream to BRAF and RAS.
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Article Source: [http://EzineArticles.com/?AZD6244---Regulates-The-Downstream-Kinases-To-BRAF-And-RAS-&id=6662277] AZD6244 - Regulates The Downstream Kinases To BRAF And RAS