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Tyrosine Kinase Inhibitors in Leukemia and Cardiovascular Events: From Mechanism to Patient Care.
Manouchehri A, Kanu E, Mauro MJ, Aday AW, Lindner JR, Moslehi J
(2020) Arterioscler Thromb Vasc Biol 40: 301-308
MeSH Terms: Cardiovascular Diseases, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Patient Care, Protein Kinase Inhibitors, Protein-Tyrosine Kinases
Show Abstract · Added January 15, 2020
Targeted oncology therapies have revolutionized cancer treatment over the last decade and have resulted in improved prognosis for many patients. This advance has emanated from elucidation of pathways responsible for tumorigenesis followed by targeting of these pathways by specific molecules. Cardiovascular care has become an increasingly critical aspect of patient care in part because patients live longer, but also due to potential associated toxicities from these therapies. Because of the targeted nature of cancer therapies, cardiac and vascular side effects may additionally provide insights into the basic biology of vascular disease. We herein provide the example of tyrosine kinase inhibitors utilized in chronic myelogenous leukemia to illustrate this medical transformation. We describe the vascular considerations for the clinical care of chronic myelogenous leukemia patients as well as the emerging literature on mechanisms of toxicities of the individual tyrosine kinase inhibitors. We additionally postulate that basic insights into toxicities of novel cancer therapies may serve as a new platform for investigation in vascular biology and a new translational research opportunity in vascular medicine.
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6 MeSH Terms
Variable Response to ALK Inhibitors in NSCLC with a Novel MYT1L-ALK Fusion.
Tsou TC, Gowen K, Ali SM, Miller VA, Schrock AB, Lovly CM, Reckamp KL
(2019) J Thorac Oncol 14: e29-e30
MeSH Terms: Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Nerve Tissue Proteins, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases, Transcription Factors
Added September 10, 2020
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AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.
Maacha S, Hong J, von Lersner A, Zijlstra A, Belkhiri A
(2018) Neoplasia 20: 1008-1022
MeSH Terms: Adenocarcinoma, Animals, Benzocycloheptenes, Biological Transport, Cathepsin B, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane, Epithelial-Mesenchymal Transition, Esophageal Neoplasms, Gene Expression Regulation, Neoplastic, Humans, Hydrogen-Ion Concentration, Lactates, Lysosomes, Monocarboxylic Acid Transporters, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Symporters, Triazoles
Show Abstract · Added April 10, 2019
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-κB-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.
Wang W, Lollis EM, Bordeleau F, Reinhart-King CA
(2019) FASEB J 33: 1199-1208
MeSH Terms: Adherens Junctions, Animals, Antigens, CD, Cadherins, Capillary Permeability, Chick Embryo, Endothelium, Vascular, Enzyme Activation, Extracellular Matrix, Female, Focal Adhesion Protein-Tyrosine Kinases, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Transgenic, Phosphorylation, Protein Transport, Tyrosine, src-Family Kinases
Show Abstract · Added April 10, 2019
Tumor vasculature is known to be more permeable than the vasculature found in healthy tissue, which in turn can lead to a more aggressive tumor phenotype and impair drug delivery into tumors. While the stiffening of the stroma surrounding solid tumors has been reported to increase vascular permeability, the mechanism of this process remains unclear. Here, we utilize an in vitro model of tumor stiffening, ex ovo culture, and a mouse model to investigate the molecular mechanism by which matrix stiffening alters endothelial barrier function. Our data indicate that the increased endothelial permeability caused by heightened matrix stiffness can be prevented by pharmaceutical inhibition of focal adhesion kinase (FAK) both in vitro and ex ovo. Matrix stiffness-mediated FAK activation determines Src localization to cell-cell junctions, which then induces increased vascular endothelial cadherin phosphorylation both in vitro and in vivo. Endothelial cells in stiff tumors have more activated Src and higher levels of phosphorylated vascular endothelial cadherin at adherens junctions compared to endothelial cells in more compliant tumors. Altogether, our data indicate that matrix stiffness regulates endothelial barrier integrity through FAK activity, providing one mechanism by which extracellular matrix stiffness regulates endothelial barrier function. Additionally, our work also provides further evidence that FAK is a promising potential target for cancer therapy because FAK plays a critical role in the regulation of endothelial barrier integrity.-Wang, W., Lollis, E. M., Bordeleau, F., Reinhart-King, C. A. Matrix stiffness regulates vascular integrity through focal adhesion kinase activity.
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19 MeSH Terms
Mechanisms of receptor tyrosine kinase activation in cancer.
Du Z, Lovly CM
(2018) Mol Cancer 17: 58
MeSH Terms: Animals, Cell Transformation, Neoplastic, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Ligands, Molecular Targeted Therapy, Mutation, Neoplasms, Phosphorylation, Protein Binding, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors, Protein Multimerization, Receptor Protein-Tyrosine Kinases, Signal Transduction
Show Abstract · Added September 10, 2020
Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.
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Quantitative Structure-Activity Relationship Modeling of Kinase Selectivity Profiles.
Kothiwale S, Borza C, Pozzi A, Meiler J
(2017) Molecules 22:
MeSH Terms: Adenosine Triphosphate, Area Under Curve, Binding Sites, Databases, Pharmaceutical, Drug Discovery, Models, Molecular, Neural Networks, Computer, Protein Binding, Protein Conformation, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Quantitative Structure-Activity Relationship, ROC Curve, Software
Show Abstract · Added November 2, 2017
The discovery of selective inhibitors of biological target proteins is the primary goal of many drug discovery campaigns. However, this goal has proven elusive, especially for inhibitors targeting the well-conserved orthosteric adenosine triphosphate (ATP) binding pocket of kinase enzymes. The human kinome is large and it is rather difficult to profile early lead compounds against around 500 targets to gain an upfront knowledge on selectivity. Further, selectivity can change drastically during derivatization of an initial lead compound. Here, we have introduced a computational model to support the profiling of compounds early in the drug discovery pipeline. On the basis of the extensive profiled activity of 70 kinase inhibitors against 379 kinases, including 81 tyrosine kinases, we developed a quantitative structure-activity relation (QSAR) model using artificial neural networks, to predict the activity of these kinase inhibitors against the panel of 379 kinases. The model's performance in predicting activity ranges from 0.6 to 0.8 depending on the kinase, from the area under the curve (AUC) of the receiver operating characteristics (ROC). The profiler is available online at http://www.meilerlab.org/index.php/servers/show?s_id=23.
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14 MeSH Terms
miR-27 regulates chondrogenesis by suppressing focal adhesion kinase during pharyngeal arch development.
Kara N, Wei C, Commanday AC, Patton JG
(2017) Dev Biol 429: 321-334
MeSH Terms: Animal Fins, Animals, Branchial Region, Cartilage, Cell Differentiation, Cell Proliferation, Cell Survival, Chondrogenesis, Embryo, Nonmammalian, Focal Adhesion Protein-Tyrosine Kinases, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, MicroRNAs, Morphogenesis, Neural Crest, Zebrafish
Show Abstract · Added August 4, 2017
Cranial neural crest cells are a multipotent cell population that generate all the elements of the pharyngeal cartilage with differentiation into chondrocytes tightly regulated by temporal intracellular and extracellular cues. Here, we demonstrate a novel role for miR-27, a highly enriched microRNA in the pharyngeal arches, as a positive regulator of chondrogenesis. Knock down of miR-27 led to nearly complete loss of pharyngeal cartilage by attenuating proliferation and blocking differentiation of pre-chondrogenic cells. Focal adhesion kinase (FAK) is a key regulator in integrin-mediated extracellular matrix (ECM) adhesion and has been proposed to function as a negative regulator of chondrogenesis. We show that FAK is downregulated in the pharyngeal arches during chondrogenesis and is a direct target of miR-27. Suppressing the accumulation of FAK in miR-27 morphants partially rescued the severe pharyngeal cartilage defects observed upon knock down of miR-27. These data support a crucial role for miR-27 in promoting chondrogenic differentiation in the pharyngeal arches through regulation of FAK.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Managing Resistance to EFGR- and ALK-Targeted Therapies.
Lovly CM, Iyengar P, Gainor JF
(2017) Am Soc Clin Oncol Educ Book 37: 607-618
MeSH Terms: Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung, Drug Resistance, Neoplasm, ErbB Receptors, Humans, Molecular Targeted Therapy, Mutation, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases
Show Abstract · Added September 10, 2020
Targeted therapies have transformed the management of non-small cell lung cancer (NSCLC) and placed an increased emphasis on stratifying patients on the basis of genetic alterations in oncogenic drivers. To date, the best characterized molecular targets in NSCLC are the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Despite steady advances in targeted therapies within these molecular subsets, however, acquired resistance to therapy is near universal. Recent preclinical models and translational efforts have provided critical insights into the molecular mechanisms of resistance to EGFR and ALK inhibitors. In this review, we present a framework for understanding resistance to targeted therapies. We also provide overviews of the molecular mechanisms of resistance and strategies to overcome resistance among EGFR-mutant and ALK-rearranged lung cancers. To date, these strategies have centered on the development of novel next-generation inhibitors, rationale combinations, and use of local ablative therapies, such as radiotherapy.
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Expression of receptor-type protein tyrosine phosphatase in developing and adult renal vasculature.
Takahashi K, Kim R, Lauhan C, Park Y, Nguyen NG, Vestweber D, Dominguez MG, Valenzuela DM, Murphy AJ, Yancopoulos GD, Gale NW, Takahashi T
(2017) PLoS One 12: e0177192
MeSH Terms: Animals, Endothelium, Vascular, Kidney, Mice, Phosphorylation, Promoter Regions, Genetic, Protein Tyrosine Phosphatases, Receptor Protein-Tyrosine Kinases
Show Abstract · Added April 6, 2018
Renal vascular development is a coordinated process that requires ordered endothelial cell proliferation, migration, intercellular adhesion, and morphogenesis. In recent decades, studies have defined the pivotal role of endothelial receptor tyrosine kinases (RPTKs) in the development and maintenance of renal vasculature. However, the expression and the role of receptor tyrosine phosphatases (RPTPs) in renal endothelium are poorly understood, though coupled and counterbalancing roles of RPTKs and RPTPs are well defined in other systems. In this study, we evaluated the promoter activity and immunolocalization of two endothelial RPTPs, VE-PTP and PTPμ, in developing and adult renal vasculature using the heterozygous LacZ knock-in mice and specific antibodies. In adult kidneys, both VE-PTP and PTPμ were expressed in the endothelium of arterial, glomerular, and medullary vessels, while their expression was highly limited in peritubular capillaries and venous endothelium. VE-PTP and PTPμ promoter activity was also observed in medullary tubular segments in adult kidneys. In embryonic (E12.5, E13.5, E15.5, E17.5) and postnatal (P0, P3, P7) kidneys, these RPTPs were expressed in ingrowing renal arteries, developing glomerular microvasculature (as early as the S-shaped stage), and medullary vessels. Their expression became more evident as the vasculatures matured. Peritubular capillary expression of VE-PTP was also noted in embryonic and postnatal kidneys. Compared to VE-PTP, PTPμ immunoreactivity was relatively limited in embryonic and neonatal renal vasculature and evident immunoreactivity was observed from the P3 stage. These findings indicate 1) VE-PTP and PTPμ are expressed in endothelium of arterial, glomerular, and medullary renal vasculature, 2) their expression increases as renal vascular development proceeds, suggesting that these RPTPs play a role in maturation and maintenance of these vasculatures, and 3) peritubular capillary VE-PTP expression is down-regulated in adult kidneys, suggesting a role of VE-PTP in the development of peritubular capillaries.
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SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer.
Ichihara E, Westover D, Meador CB, Yan Y, Bauer JA, Lu P, Ye F, Kulick A, de Stanchina E, McEwen R, Ladanyi M, Cross D, Pao W, Lovly CM
(2017) Cancer Res 77: 2990-3000
MeSH Terms: Acrylamides, Aniline Compounds, Animals, Antineoplastic Agents, Drug Resistance, Neoplasm, ErbB Receptors, Female, Focal Adhesion Protein-Tyrosine Kinases, Humans, Lung Neoplasms, Mice, Mice, Nude, Mutation, Piperazines, Signal Transduction, Transfection, src-Family Kinases
Show Abstract · Added September 10, 2020
Mutant-selective EGFR tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of -mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first- and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with -mutant lung cancer. Despite promising results, therapeutic efficacy is limited by the development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and MAPK pathway signaling under continuous EGFR inhibition in osimertinib-sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member was amplified in osimertinib-resistant -mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that the concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for -mutant lung cancer. .
©2017 American Association for Cancer Research.
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