MEK/ERK pathways and MCT-1 in Diffuse Large B-cell Lymphoma

Baltimore Va Medical Center, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Translation initiation is known to be a common downstream target of signal transduction pathways deregulated in cancer and initiated by mutated/overexpressed oncogenes and tumor suppressors. There is a growing body of evidence linking deregulated translation on the causal pathway to cancer. Therefore, it is reasonable to assume that the downstream translation step provides a major contribution to tumorgenesis induced by activated oncogenic pathways and that this oncogenic addiction may serve as an Achilles heel in the treatment of malignancies. MCT-1, an oncogene involved in translational regulation has recently been shown by the Gartenhaus laboratory to be overexpressed in the vast majority of primary diffuse large B-cell lymphomas (DLBCL). Knocking down MCT-1 protein levels in DLBCL significantly reduced cell viability through an apoptotic mechanism, providing the first direct genetic evidence that interfering with MCT-1 function was able to induce apoptosis in lymphoma cells with high endogenous levels of MCT-1 protein. MCT-1 protein interacts with the cap complex, which recruits Density Regulated Protein (DENR) protein, containing an SUI1 domain. The recruitment of DENR has been shown to increase the translation initiation of a subset of mRNAs (translatome), containing a long and highly structured 5' UTR, typically found in cancer related messages. While there are no specific small molecule inhibitors that can directly inhibit MCT-1 at present, its activity has been shown to be regulated by MEK/ERK kinases. Previous work from our group has shown that MCT-1 physically associates with ERK and that disruption of this protein-protein interaction provides a novel targeted approach to treat DLBCL. Furthermore, inhibition of MEK/ERK blocks the phosphorylation and biological activity of MCT-1, further establishing the functional interaction between MCT-1 and the MEK/ERK pathway. Several strategies have been developed to suppress MEK/ERK, however few small-molecule MEK inhibitors have become clinically available. Moreover, this strategy has never been extensively evaluated in lymphoma. We currently have full access to a selective and potent 2nd generation small-molecule MEK inhibitor, AZD-6244. This presents a unique opportunity to target a translational regulatory protein critical to lymphomagenesis. The objective of this application is to investigate the importance of the MEK/ERK pathway and the associated interaction(s) with MCT-1 towards B-cell lymphomagenesis in vitro and in vivo tumor models. The central hypothesis of this proposal is that the MEK/ERK signaling plays a critical role in regulating the stability and activity of the MCT-1 protein in DLBCL and that interruption of MEK/ERK/MCT-1 function with a novel targeted MEK inhibitor will effectively repress the lymphoma phenotype. Furthermore, the molecular characterization of the genetic networks of DLBCL will help us to understand how perturbation of MEK/ERK/MCT-1 regulated genes contributes to lymphomagenesis. The rationale for the proposed research is that MCT-1 and the MEK/ERK pathway have been shown to be important survival pathways in lymphoma and that newer more potent small-molecule MEK inhibitors are now available. We have shown in preliminary experiments that the selective MEK inhibitor, AZD-6244, inhibited proliferation and induced dose-dependent apoptosis at nanomolar concentrations in DLBCL cell lines, primary cells, and in a human lymphoma xenograft model.