A5006811358- Melanoma and MAPK Pathways
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Cancer, Hypoxia, and Metabolism
- Growth Hormone and Insulin-like Growth Factors
- Cancer-related Molecular Pathways
- Biochemical and Molecular Research
- Multiple Myeloma Research and Treatments
- Protein Tyrosine Phosphatases
- Cancer Immunotherapy and Biomarkers
- Protein Kinase Regulation and GTPase Signaling
- HER2/EGFR in Cancer Research
- Asthma and respiratory diseases
- Metabolism, Diabetes, and Cancer
- Chronic Lymphocytic Leukemia Research
- Genomics and Chromatin Dynamics
- Advanced Breast Cancer Therapies
- RNA Research and Splicing
- Immune Cell Function and Interaction
- Mast cells and histamine
- Fibroblast Growth Factor Research
- Cancer Mechanisms and Therapy
- Extracellular vesicles in disease
- Signaling Pathways in Disease
- Cell Adhesion Molecules Research
Molecular Partners (Switzerland)
2023-2024
Merck (Germany)
2019-2022
Boehringer Ingelheim (Austria)
2011-2021
Boehringer Ingelheim (Germany)
2009-2015
University of Massachusetts Chan Medical School
2012
University Health Network
2009
University of Toronto
2009
German Cancer Research Center
2006-2007
Heidelberg University
2006-2007
Cooperative Research Centre for Tissue Growth and Repair
2004-2006
Deregulation of the ErbB (proto-oncogene B avian erythroblastosis virus AEV-H strain) receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small-molecule kinase inhibitors, each them characterized by distinct patterns interactions. Understanding precise pharmacological properties these compounds important for optimal use clinical practice. Afatinib [BIBW 2992;...
Ectodomain shedding is a proteolytic mechanism by which transmembrane molecules are converted into soluble form. Cleavage mediated metalloproteases and proceeds in constitutive or inducible fashion. Although believed to be cell-surface event, there increasing evidence that cleavage can take place intracellular compartments. However, it unknown how cleaved get access the extracellular space. By analysing L1 (CD171) CD44 ovarian carcinoma cells, we show present paper induced ionomycin, APMA...
Exosomes are small membrane vesicles derived from intracellular multivescicular bodies (MVBs) that can undergo constitutive and regulated secretion cells. also secrete soluble proteins through metalloprotease-dependent ectodomain shedding. In this study, we sought to determine whether ErbB1 receptors present within exosomes isolated the human keratinocyte cell line, HaCaT, exosome-associated further proteolytic processing. We show full-length transmembrane is secreted in HaCaT exosomes. EGF...
Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response inhibitory drugs, yet its role in nucleus poorly characterized. Here, we investigated significance cancers and cell line models. In prostate cancers, was predominantly membrane localized benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic)...
Abstract Natural killer (NK) cells play a pivotal role in controlling cancer. Multiple extracellular receptors and internal signaling nodes tightly regulate NK activation. Cyclin-dependent kinases of the mediator complex (CDK8 CDK19) were described as intermediates cells. Here, we report for first time development use CDK8/19 inhibitors to suppress phosphorylation STAT1S727 augment production cytolytic molecules perforin granzyme B (GZMB). Functionally, this resulted enhanced...
KRAS, the most common oncogenic driver in human cancers, is controlled and signals primarily through protein-protein interactions (PPIs). The interaction between KRAS SOS1, crucial for activation of a typical, challenging PPI with large contact surface area high affinity. Here, we report that addition only one atom placed Y884SOS1 A73KRAS sufficient to convert SOS1 activators into inhibitors. We also disclose discovery BI-3406. Combination upstream EGFR inhibitor afatinib shows vivo efficacy...
Betacellulin belongs to the family of epidermal growth factor-like factors that are expressed as transmembrane precursors and undergo proteolytic ectodomain shedding release a soluble mature factor. In this study, we investigated betacellulin precursor (pro-BTC) in conditionally immortalized wild-type (WT) ADAM-deficient cell lines. Sequential cleavage predominant cell-surface 40-kDa form pro-BTC generated major (26-28 kDa) two minor (20 15 forms cellular remnant lacking (12 kDa). Pro-BTC...
Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context FGFR1 expression and define biomarkers predictive inhibitor response. In this study, 635 samples were characterised for protein by immunohistochemistry copy number...
Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (β1, β2, and β5). LMP7 (β5i) is a subunit immunoproteasome, an inducible isoform that predominantly in hematopoietic cells. Clinically effective pan-proteasome inhibitors for treatment multiple myeloma (MM) nonselectively target other constitutive proteasome immunoproteasome with comparable potency, which can limit therapeutic applicability these...
Abstract Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, contributes to degradation ubiquitinated proteins. Described herein for first time preclinical profile M3258; an orally bioavailable, potent, reversible highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy myeloma xenograft models, novel model human bone...
Abstract The spleen tyrosine kinase (Syk) is a key mediator of immunoreceptor signaling in immune cells. Thus, interfering with the function Syk by genetic deletion or pharmacological inhibition might influence variety allergic and autoimmune processes. Since conventional knockout mice are not viable, studies addressing effect adult animals have been limited. To further explore functions animal models allergy to shed light on role vivo migration neutrophils monocytes, we generated inducible...
Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, identification selection biomarkers for enrichment potential responders represents a high priority future trials these agents. Several reports described IGF2 expression subset colorectal cancers, focal amplification responsible some cases. We defined novel cut-off value...
Abstract Inhibition of the IGF1R, INSRA, and INSRB receptor tyrosine kinases represents an attractive approach pharmacologic intervention in cancer, owing to roles IGF1R INSRA promoting cell proliferation survival. However, central role isoform glucose homeostasis suggests that prolonged inhibition this kinase could result metabolic toxicity. We describe here profile novel compound BI 885578, a potent selective ATP-competitive IGF1R/INSR inhibitor distinguished by rapid intestinal absorption...
Tepotinib is an oral MET inhibitor approved for metastatic non-small cell lung cancer (NSCLC) harboring exon 14 (METex14) skipping mutations. Examining treatment-naive or tepotinib-resistant cells with amplification METex14 mutations identifies other receptor tyrosine kinases (RTKs) that co-exist in prior to tepotinib exposure and become more prominent upon resistance. In a small cohort of patients genetic alterations treated tepotinib, gene copy number gains RTKs were found at baseline...
Abstract The betacellulin precursor (pro‐BTC) is a novel substrate for ADAM10‐mediated ectodomain shedding. In this report, we investigated the ability of physiologically relevant stimuli, including G‐protein coupled receptor (GPCR) agonists and reactive oxygen species (ROS), to stimulate pro‐BTC We found that in breast adenocarcinoma MCF7 cells overexpressing pro‐BTC, hydrogen peroxide (H 2 O ) was powerful stimulator stimulation shedding by H blocked broad‐spectrum metalloprotease...