The target landscape of clinical kinase drugs Klaeger, Susan; Heinzlmeir, Stephanie; Wilhelm, Mathias ...
Science (American Association for the Advancement of Science),
12/2017, Letnik:
358, Številka:
6367
Journal Article
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Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, ...we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
Nucleotide-binding and oligomerization domain (NOD)-like receptors constitute a first line of defense against invading bacteria. X-linked Inhibitor of Apoptosis (XIAP) is implicated in the control of ...bacterial infections, and mutations in XIAP are causally linked to immunodeficiency in X-linked lymphoproliferative syndrome type-2 (XLP-2). Here, we demonstrate that the RING domain of XIAP is essential for NOD2 signaling and that XIAP contributes to exacerbation of inflammation-induced hepatitis in experimental mice. We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2. We further show that LUBAC activity is required for efficient NF-κB activation and secretion of proinflammatory cytokines after NOD2 stimulation. Remarkably, XLP-2-derived XIAP variants have impaired ubiquitin ligase activity, fail to ubiquitylate RIPK2, and cannot facilitate NOD2 signaling. We conclude that XIAP and LUBAC constitute essential ubiquitin ligases in NOD2-mediated inflammatory signaling and propose that deregulation of NOD2 signaling contributes to XLP-2 pathogenesis.
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▸ XIAP is required for NOD2-dependent signaling and inflammation in vivo ▸ XIAP ubiquitylates RIPK2 after NOD2 stimulation to facilitate LUBAC recruitment ▸ LUBAC regulates NOD2-dependent immune signaling ▸ XLP-2-derived XIAP mutations impair ubiquitin ligase activity and NOD2 signaling
Activation of NF-κB transcription factors by receptors of the innate or adaptive immune system is essential for host defense. However, after danger is eliminated, NF-κB signaling needs to be tightly ...downregulated for the maintenance of tissue homeostasis. This review highlights key negative regulatory principles that affect the amount, localization or conformational properties of NF-κB-activating proteins to attenuate the NF-κB response. These mechanisms are needed to prevent inflammation, autoimmune disease and oncogenesis.
CARD protein-BCL-10-MALT1 (CBM) signalosomes are multiprotein signalling platforms that control immune and inflammatory pathways in most tissues. After exposure to distinct immune triggers, these ...molecules form self-organizing filaments with MALT1 protease activity to regulate canonical nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways and the degradation of mRNA-binding proteins, which provides two layers of control of inflammatory gene expression. These CBM-regulated mechanisms are essential for host defence and tissue homeostasis, and numerous genetic alterations in CBM signalling components have been implicated in inherited and acquired immune-mediated diseases. This Review discusses the regulation and signalling of CBM complexes, their physiological roles and their pathophysiological functions in human immunodeficiency diseases, inflammatory disorders and cancers of the immune system.
In this issue of Cancer Cell, Jackstadt et al. report that pathological Notch signaling in colorectal cancer (CRC) cells can initiate a neutrophil-dependent, TGF-β-mediated cascade that leads to ...metastatic disease. Inhibition of this pathway with clinically relevant compounds blocks metastatic spread in a developed murine model of CRC.
In this issue of Cancer Cell, Jackstadt et al. report that pathological Notch signaling in colorectal cancer (CRC) cells can initiate a neutrophil-dependent, TGF-β-mediated cascade that leads to metastatic disease. Inhibition of this pathway with clinically relevant compounds blocks metastatic spread in a developed murine model of CRC.
Microbial and danger signals result in inflammasome activation and release of inflammatory cytokines through mechanisms that remain elusive. Cai et al. and Lu et al. show that triggering of ...inflammasome sensors induces prion-like polymerization of the adaptor ASC into filaments. These structures function as platforms for inflammatory cytokine production and represent a unified mechanism for inflammasome assembly.
The inhibitory receptor PD-1 is critical to balancing antigen-induced T cell activation; its inhibition is currently being explored to enhance antitumor T cell immunity with certain successful ...outcomes. However, PD-1 has also emerged as a central tumor suppressor in T cell lymphomas, where the tumor cell originates from a T cell itself. These aggressive cancers are frequently characterized by oncogenic mutations in T cell receptor (TCR) signaling pathways. PD-1 activity within malignant T cells can negatively regulate the PI3K/AKT and PKCθ/NF-κB tumor survival pathways and PD-1 is frequently inactivated in this human malignancy. This review summarizes current insights into oncogenic T cell signaling, discusses tumor-suppressive functions and mechanisms of PD-1 in T cell lymphomagenesis, and addresses potential unwanted effects caused by PD-1 checkpoint inhibition.
T cell lymphomas are aggressive cancers characterized by oncogenic mutations in TCR signaling pathways.
PD-1 is a central tumor suppressor in T cell lymphoma that is frequently inactivated in human T-NHL.
PD-1 activity within malignant human and mouse T cells can negatively regulate the PI3K/AKT and PKCθ/NF-κB tumor survival pathways.
PD-1 targeting checkpoint inhibitors can also accelerate T cell lymphomas under still-undefined conditions.
Highlights ► Card9 integrates signals from multiple PRRs. ► Card9 drives proinflammatory responses. ► Card9 is essential for host protection. ► Polymorphisms in Card9 are detected in inflammatory ...disease.
T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently ...characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.
Spleen tyrosine kinase (SYK) is known to have a crucial role in adaptive immune receptor signalling. However, recent reports indicate that SYK also mediates other, unexpectedly diverse biological ...functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. SYK is activated by C-type lectins and integrins, and activates new targets, including the CARD9-BCL-10-MALT1 pathway and the NLRP3 inflammasome. Studies using Drosophila melanogaster suggest that there is an evolutionarily ancient origin of SYK-mediated signalling. Moreover, SYK has a crucial role in autoimmune diseases and haematological malignancies. This Review summarizes our current understanding of the diverse functions of SYK and how this is being translated for therapeutic purposes.
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