A5061354302- Mechanisms of cancer metastasis
- Cell death mechanisms and regulation
- Melanoma and MAPK Pathways
- Cancer Genomics and Diagnostics
- PI3K/AKT/mTOR signaling in cancer
- Peptidase Inhibition and Analysis
- Cancer Mechanisms and Therapy
- Protease and Inhibitor Mechanisms
- Cancer-related Molecular Pathways
- Graphene and Nanomaterials Applications
- Ubiquitin and proteasome pathways
- Protein Tyrosine Phosphatases
- Protein Kinase Regulation and GTPase Signaling
- Protein Degradation and Inhibitors
- Lung Cancer Treatments and Mutations
- Microtubule and mitosis dynamics
- Genetics, Bioinformatics, and Biomedical Research
- Colorectal Cancer Treatments and Studies
- Computational Drug Discovery Methods
- Chronic Lymphocytic Leukemia Research
- Hippo pathway signaling and YAP/TAZ
- Genomics and Rare Diseases
- Chronic Myeloid Leukemia Treatments
- Genetic factors in colorectal cancer
- Click Chemistry and Applications
Frederick National Laboratory for Cancer Research
2017-2025
National Cancer Institute
2005-2025
Center for Cancer Research
2002-2025
National Institutes of Health
2003-2025
Office of Extramural Research
2018-2022
Gdańsk Medical University
2019
Warsaw University of Technology
2019
Medical University of Warsaw
2019
Postgraduate School of Molecular Medicine
2019
University of Warsaw
2019
Tobacco-related diseases such as lung cancer cause over 4.2 million deaths annually, with approximately 400,000 per year occurring in the US. Genotoxic effects of tobacco components have been described, but on signaling pathways normal cells not described. Here, we show activation serine/threonine kinase Akt nonimmortalized human airway epithelial vitro by two cigarette smoke, nicotine and tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Activation or NNK...
Tobacco-related diseases such as lung cancer cause over 4.2 million deaths annually, with approximately 400,000 per year occurring in the US. Genotoxic effects of tobacco components have been described, but on signaling pathways normal cells not described. Here, we show activation serine/threonine kinase Akt nonimmortalized human airway epithelial vitro by two cigarette smoke, nicotine and tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Activation or NNK...
BRAF and MEK inhibitors are effective in mutant melanoma, but most patients eventually relapse with acquired resistance, others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family (SFK) signaling or NRAS, which drive paradoxical of the pathway. We describe pan-RAF (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not activation MEK/ERK NRAS melanoma. They melanoma cells...
Retrospective studies have shown that patients with tobacco-related cancers who continue to smoke after their diagnoses lower response rates and shorter median survival compared stop smoking. To provide insight into the biologic basis for these clinical observations, we tested whether two tobacco components, nicotine or tobacco-specific carcinogen, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), could activate Akt pathway increase lung cancer cell proliferation survival. Nicotine NNK,...
The synthesis from l-quebrachitol of a series 3-deoxygenated ether lipid-type phosphatidylinositol (PI) analogues is reported, that selectively block activation Akt and downstream substrates without affecting the upstream kinase, PDK-1, or other kinases ras such as MAPK in H157 H1703 lung cancer cells have high levels constitutively active Akt. 2-hydroxyl these compounds was deleted alkylated with intent to preclude metabolic degradation by PI-specific phospholipase C (PI-PLC). PI phosphate...
Objective Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that assumed to occur via complex interplay of environmental and genetic factors. Rare causes monogenic SLE have been described, providing unique insights into fundamental mechanisms immune tolerance. The aim this study was identify the cause an autosomal‐recessive form SLE. Methods We studied 3 siblings with juvenile‐onset from 1 consanguineous kindred used next‐generation sequencing mutations in...
Abstract Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself other proteins. Several inhibitors currently employed the clinic or undergoing trials for treatment of various cancers. These drugs act primarily trapping on damaged chromatin, which can lead to cell death, especially cells with repair defects. Although is thought be caused catalytic inhibition PARP-dependent modification,...
The worldwide annual frequency and lethality of head neck squamous cell carcinoma (HNSCC) is not improving, thus, new therapeutic approaches are needed. Approximately 70% HNSCC cases have either amplification or overexpression MAP3K13 , which encodes the kinase LZK. Here, we found that LZK a target in small-molecule inhibition its catalytic function decreased viability cells with amplified . Inhibition suppressed tumor growth -amplified xenografts derived from patients. stabilized...
Abstract RAF inhibitor therapy yields significant reductions in tumour burden the majority of V600E-positive melanoma patients; however, resistance occurs within 2–18 months. Here we demonstrate that mixed lineage kinases (MLK1–4) are MEK reactivate MEK/ERK pathway presence inhibitors. Expression MLK1–4 mediates to inhibitors and promotes survival cell lines. Furthermore, observe upregulation MLKs 9 21 patients with acquired drug resistance. Consistent this observation, promote mouse models...
Activation of the PI3k/Akt pathway controls key cellular processes and contributes to tumorigenesis in vivo, but investigation has been limited by lack specific inhibitors directed against Akt. To develop Akt inhibitors, we used molecular modeling pleckstrin homology (PH) domain guide synthesis structurally modified phosphatidylinositol ether lipid analogues (PIAs). Here, characterize biochemical effects PIAs. Of 24 compounds tested, five PIAs with modifications at two sites on inositol ring...
Abstract Cancer kinome sequencing studies have identified several protein kinases predicted to possess driver (i.e., causal) mutations. Using bioinformatic applications, we pinpointed DAPK3 (ZIPK) as a novel cancer-associated kinase with functional Evaluation of nonsynonymous point mutations, discovered in various tumors (T112M, D161N, and P216S), reveals that all three mutations decrease or abolish activity. Furthermore, phenotypic assays indicate the observed cancer abrogate function...
Approximately 70% of patients with non–small-cell lung cancer present late-stage disease and have limited treatment options, so there is a pressing need to develop efficacious targeted therapies for these patients. This remains major challenge as the underlying genetic causes ∼50% cancers remain unknown. Here we demonstrate that dependency screen an efficient approach identify somatic alterations are functionally important. By using this approach, identified three kinases gain-of-function...
Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for treatment LSCC. Distal amplification 3q chromosome frequent alteration in LSCC, and there an urgent need to identify efficacious druggable targets within this amplicon. We protein kinase TNIK as a therapeutic target amplified approximately 50% LSCC cases. genetic depletion or pharmacologic inhibition reduces growth cells...
Abstract MLK4 is a member of the mixed-lineage family kinases that regulate JNK, p38, and ERK kinase signaling pathways. mutations have been identified in various human cancers, including frequently colorectal cancer, where their function pathobiological importance uncertain. In this study, we assessed functional consequences colon tumorigenesis. Biochemical data indicated majority are loss-of-function (LOF) can exert dominant-negative effects. seeking to understand abrogated activity these...
Significance This work unveils how an Alzheimer’s disease-associated mutation (M489V) in protein kinase Cα (PKCα) enhances catalytic activity without sensitizing the to cell’s homeostatic degradation of aberrantly active PKCα. The conformation wild-type PKC is sensitive degradation, and therefore constitutively activated paradoxically manifests as loss function. We show that PKCα-M489V intrinsic rate altering equilibrium between autoinhibited (protected) (degradation-sensitive) conformation....