Identification of TAK1, a MAP3K7 as a novel target in non Hodgkin’s lymphomas

4121 Different subtypes of lymphomas account for a significant proportion of human malignancies. Although there is reasonable success in the clinic with anti-CD20 antibodies, there is a paucity of targeted therapeutic agents. In our search for novel targets of relevance in non-Hodgkin’s lymphoma, we have identified MAP3K7, TAK1 as a critical kinase contributing to the survival of a subset of diffuse large B-cell lymphoma cells. TAK1 is a “multitasking kinase” as it acts in a signaling nexus that responds to a variety of upstream signals stimulated by agents, including but not limited to proinflammatory cytokines, antigens and microbial products in a variety of cell systems. In response to these stimuli, ubiquitin-activated TAK1, phosphorylates IKK and MAP kinases ultimately leading to the activation of the transcription factors NF-kB and AP-1.
 We have used several complementary genetic, small molecule, and phospho-profiling approaches to validate TAK1 as a novel target in distinct subtypes of lymphomas. Inhibition of TAK1 expression via TAK1 selective shRNA was found to compromise survival of a distinct class of non-Hodgkin’s lymphoma cells. Furthermore, inhibition of TAK1 kinase activity via small molecule ATP competitive inhibitors displayed similar selectivity in a large panel of Haem-Onc cell lines while having minimal effects on multiple myeloma cells. The mechanism of inhibition of survival by the small molecule inhibitor is consistent with its ability to modulate apoptosis. In another approach using reverse phase protein array pathway profiling we have identified that the TAK1 pathways are significantly activated in a set of lymphoma cells. In addition, Geneset enrichment analysis suggests that TAK1 related pathways are deregulated in DLBCL and the de-regulation is associated with DLBCL subtypes. Finally, unsupervised 2-way clustering performed using the same gene expression data set and the same TAK1 related pathway gene set clearly separated the DLBCL samples into 3 subgroups, while the multiple myeloma samples did not separate in to any subgroups. TAK1 is thus identified as a novel target in non-Hodgkin’s Lymphomas.