Tpl-2 and MEK small molecule inhibitors
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ABSTRACT:
PROVIDER: PRJNA328166 | ENA |
REPOSITORIES: ENA
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Project description:Tpl-2 is a serine/threonine kinase that has been studied extensively in monocytes. Tpl-2 is believed to phosphorylate MEK1/2, which is upstream of ERK1/2, and regulates inflammatory gene expression in response to TLR and IL-1b receptor signaling. In the course of performing proof-of-concept studies using a small molecule inhibitor (SMI) of Tpl-2, we were surprised to see the inhibitor affect cytokine production in human neutrophils. Unlike human monocytes, which respond at least some degree to both Tpl-2 and MEK inhibitors, neutrophils showed a disconnect between Tpl-2 and MEK. A panel of genes in this cell type can be fully blocked by a Tpl-2 SMI, and yet show no response to a MEK SMI, suggesting Tpl-2 mediates its effect through substrates other than MEK.
2019-07-01 | GSE84153 | GEO
Project description:Comparison of Tpl-2 small molecule inhibitor (SMI) versus MEK SMI activities in LPS-treated human monocytes will reveal a subset of genes that require Tpl-2 but are independent of MEK. Tpl-2 is a highly conserved (94% human versus mouse) serine-threonine kinase expressed in cells important to the inflammatory response, including monocytes, macrophages, dendritic cells, and B/T cells. The role of Tpl-2 in monocytes and macrophages has been especially well-studied. It has been shown in these cells that Tpl-2 is required for the expression of cytokines in response to Toll-like receptor ligands, including LPS. In resting cells, Tpl-2 forms a complex with p105 and ABIN-2. Upon stimulation, this complex dissociates. Dissociated p105 is processed to p50, which impacts transcription. Dissociated Tpl-2 phosphorylates MEK, which, in turn, phosphorylates ERK. ERK activates the transcription factor AP-1 and its downstream gene targets. An open question in the field is whether Tpl-2 acts solely through MEK to drive gene expression, or does Tpl-2 have any MEK-independent targets. Answering this question is important both for understanding basic Tpl-2 biology as well as its role in disease. Based on published data, Tpl-2 is important for inflammatory cytokine production, and in animal models where these cytokines contribute to disease (septic shock, IBD), blocking Tpl-2 ameliorates disease symptoms. We have a highly selective SMI of Tpl-2 that effectively blocks cytokine production in purified human monocytes. This SMI can block production of the same cytokines that a MEK inhibitor blocks, which is expected given that Tpl-2 lies upstream of MEK. However, the MEK SMI only partially inhibits certain cytokines, while the Tpl-2 SMI fully blocks them, suggesting there are additional factors downstream of Tpl-2 that are not MEK-dependent.
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Project description:Resistance to Ras pathway inhibition is a major challenge in the treatment of colorectal cancer (CRC), but the underlying mechanisms are incompletely understood. Here we performed large-scale small molecule screens in CRC and identified inhibitors of MEK1/2 as potent activators of Wnt/beta-catenin signalling. Targeting MEK increased Wnt activity in different CRC cell lines and in the murine intestine in vivo. The MEK-induced Wnt response was strongly enhanced by truncating mutations in APC and proteomic experiments identified that AXIN1 levels are depleted upon MEK inhibition. We generated patient-derived colon cancer organoids and showed that a clinically approved MEK inhibitor leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stem cells and cancer relapse. This reprogramming was reverted by co-treatment with Wnt inhibitors. Our study demonstrates that MEK inhibition affects cellular plasticity and induces an intestinal stem cell program which constitutes a novel mechanism of drug resistance.
2018-05-08 | GSE114060 | GEO
Project description:Resistance to Ras pathway inhibition is a major challenge in the treatment of colorectal cancer (CRC), but the underlying mechanisms are incompletely understood. Here we performed large-scale small molecule screens in CRC and identified inhibitors of MEK1/2 as potent activators of Wnt/beta-catenin signalling. Targeting MEK increased Wnt activity in different CRC cell lines and in the murine intestine in vivo. The MEK-induced Wnt response was strongly enhanced by truncating mutations in APC and proteomic experiments identified that AXIN1 levels are depleted upon MEK inhibition. We generated patient-derived colon cancer organoids and showed that a clinically approved MEK inhibitor leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stem cells and cancer relapse. This reprogramming was reverted by co-treatment with Wnt inhibitors. Our study demonstrates that MEK inhibition affects cellular plasticity and induces an intestinal stem cell program which constitutes a novel mechanism of drug resistance.
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Project description:Aberrant RAS/MAPK signaling, a common driver of oncogenesis, can be therapeutically targeted with clinically approved MEK inhibitors. Single agent therapy ultimately results in tumor outgrowth in most settings and combination therapies are required to achieve significant clinical benefit in most advanced cancers. Here we focus on identifying MEK inhibitor-based combination therapies in RAS-mutant neuroblastoma. Mutations that activate the RAS/MAPK signaling pathway, while rare at diagnosis, are more frequent in relapsed neuroblastoma. More than 50% of children with high-risk neuroblastoma ultimately relapse and treatment options for relapsed neuroblastoma are limited so most children with relapsed disease do not survive. Here we use a genome-scale CRISPR-Cas9 functional genomic screen to identify genes that, when lost, sensitize RAS-mutant neuroblastoma to MEK inhibition. We discover that loss of either CCNC or CDK8, two members of the mediator kinase module, sensitizes neuroblastoma to MEK inhibition. Furthermore, we demonstrate that small molecule kinase inhibitors of CDK8 improve response to MEK inhibitors in vitro and in vivo in RAS-mutant neuroblastoma and other adult solid tumors, suggesting that the addition of CDK8 inhibitors could improve clinical outcome. Using transcriptional profiling, we unexpectedly find that loss of CDK8 or CCNC antagonizes the transcriptional signature induced by MEK inhibition. When combined, loss of CDK8 or CCNC prevents the compensatory upregulation of pro-growth gene expression induced by MEK inhibition. These findings propose a new therapeutic combination for RAS-mutant neuroblastoma and may have clinical relevance for other RAS-driven malignancies.
2023-02-22 | GSE190178 | GEO
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