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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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MeSH Terms
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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Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies.
Shaver TM, Lehmann BD, Beeler JS, Li CI, Li Z, Jin H, Stricker TP, Shyr Y, Pietenpol JA
(2016) Cancer Res 76: 4850-60
MeSH Terms: Algorithms, Cell Line, Tumor, Female, Gene Expression Profiling, Gene Rearrangement, Humans, Immunoblotting, Neoplasms, Oncogene Proteins, Fusion, Polymerase Chain Reaction, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Triple Negative Breast Neoplasms, c-Mer Tyrosine Kinase
Show Abstract · Added April 9, 2017
Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high-frequency "driver" alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that affect the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3-TACC3 fusion in TNBC. Expanding our analysis to other malignancies, we identified a diverse array of novel and known hybrid transcripts, including rearrangements between noncoding regions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1 The over 1,000 genetic alterations we identified highlight the importance of considering noncoding gene rearrangement partners, and the targetable gene fusions identified in TNBC demonstrate the need to advance gene fusion detection for molecularly heterogeneous cancers. Cancer Res; 76(16); 4850-60. ©2016 AACR.
©2016 American Association for Cancer Research.
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14 MeSH Terms
Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics.
Haake SM, Li J, Bai Y, Kinose F, Fang B, Welsh EA, Zent R, Dhillon J, Pow-Sang JM, Chen YA, Koomen JM, Rathmell WK, Fishman M, Haura EB
(2016) Clin Cancer Res 22: 5605-5616
MeSH Terms: Carcinoma, Papillary, Carcinoma, Renal Cell, Cell Line, Tumor, Cell Survival, ErbB Receptors, Extracellular Matrix, Humans, Kidney Neoplasms, Mass Spectrometry, Phosphorylation, Phosphotyrosine, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Proteomics, Receptor Protein-Tyrosine Kinases, Signal Transduction, Tyrosine
Show Abstract · Added August 8, 2016
PURPOSE - Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes.
EXPERIMENTAL DESIGN - Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. To describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed.
RESULTS - Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, whereas DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets.
CONCLUSIONS - Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology among kidney cancer subtypes. Clin Cancer Res; 22(22); 5605-16. ©2016 AACR.
©2016 American Association for Cancer Research.
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17 MeSH Terms
Histology-Specific Uses of Tyrosine Kinase Inhibitors in Non-gastrointestinal Stromal Tumor Sarcomas.
Sethi TK, Keedy VL
(2016) Curr Treat Options Oncol 17: 11
MeSH Terms: Antineoplastic Agents, Bone Neoplasms, Gastrointestinal Stromal Tumors, Humans, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Sarcoma, Signal Transduction
Show Abstract · Added March 16, 2016
OPINION STATEMENT - Adult sarcomas, especially those with metastatic or unresectable disease, have limited treatment options. Traditional chemotherapeutic options have been limited by poor response rates in patients with advanced sarcomas. The important clinical question is whether the success of targeted therapy in GIST can be extended to other sarcomas and also if preclinical data describing targets across this heterogeneous group of cancers can be translated to clinical efficacy of known and upcoming target specific agents. Multi-targeted tyrosine kinase inhibitors (TKI) such as pazopanib, sorafenib, sunutinib, cediranib have shown benefits across various histologies of soft tissue sarcoma as well as bone sarcomas. The efficacy of imatinib in Dermatofibrosarcoma Protruberans; sunitinib and cediranib in alveolar soft part sarcoma; and sorafenib and imatinib in chordomas have provided a treatment option of these rare tumors where no effective options existed. TKIs are being tested in combination with chemotherapy as well as radiation to improve response. Although traditional RECIST criteria may not adequately reflect response to these targeted agents, the studies have shown promise for the efficacy of TKIs across the spectrum of sarcomas. The integration of biomarker studies with clinical trials may help further identify responders beyond that defined by histology. With the current data, TKIs are being used both as first-line treatment and beyond in non-GIST sarcomas.
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Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis.
Johung KL, Yeh N, Desai NB, Williams TM, Lautenschlaeger T, Arvold ND, Ning MS, Attia A, Lovly CM, Goldberg S, Beal K, Yu JB, Kavanagh BD, Chiang VL, Camidge DR, Contessa JN
(2016) J Clin Oncol 34: 123-9
MeSH Terms: Adult, Aged, Anaplastic Lymphoma Kinase, Antineoplastic Agents, Brain Neoplasms, Carbazoles, Carcinoma, Non-Small-Cell Lung, Cranial Irradiation, Crizotinib, Disease-Free Survival, Female, Follow-Up Studies, Gene Rearrangement, Humans, Kaplan-Meier Estimate, Karnofsky Performance Status, Lung Neoplasms, Male, Middle Aged, Molecular Targeted Therapy, Neoplasm Staging, Piperidines, Prognosis, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Pyrazoles, Pyridines, Pyrimidines, Radiosurgery, Receptor Protein-Tyrosine Kinases, Risk Assessment, Risk Factors, Smoking, Sulfones
Show Abstract · Added January 26, 2016
PURPOSE - We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis.
PATIENTS AND METHODS - A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling.
RESULTS - Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001).
CONCLUSION - Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease.
© 2015 by American Society of Clinical Oncology.
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34 MeSH Terms
Anaplastic Lymphoma Kinase as a Therapeutic Target in Non-Small Cell Lung Cancer.
Iams WT, Lovly CM
(2015) Cancer J 21: 378-82
MeSH Terms: Anaplastic Lymphoma Kinase, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Clinical Trials as Topic, Drug Resistance, Neoplasm, Humans, Lung Neoplasms, Molecular Targeted Therapy, Mutation, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases, Recombination, Genetic, Translocation, Genetic, Treatment Outcome
Show Abstract · Added January 26, 2016
The therapeutic targeting of anaplastic lymphoma kinase (ALK) has been a burgeoning area of research since 2007 when ALK fusions were initially identified in patients with non-small cell lung cancer. The field has rapidly progressed through development of the first-generation ALK inhibitor, crizotinib, to an understanding of mechanisms of acquired resistance to crizotinib and is currently witnessing an explosion in the development of next-generation ALK inhibitors such as ceritinib, alectinib, PF-06463922, AP26113, X-396, and TSR-011. As with most targeted therapies, acquired resistance appears to be an inevitable outcome. Current preclinical and clinical studies are focused on the development of rational therapeutic strategies, including novel ALK inhibitors, as well as rational combination therapies to maximize disease control by delaying or overcoming acquired therapeutic resistance. This review summarizes the existing clinical data and ongoing research pertaining to the clinical application of ALK inhibitors in patients with non-small cell lung cancer.
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RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.
Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S, Blakely CM, Okimoto RA, Lin L, Neel DS, Sabnis A, Flanagan J, Chan E, Varella-Garcia M, Aisner DL, Vaishnavi A, Ou SH, Collisson EA, Ichihara E, Mack PC, Lovly CM, Karachaliou N, Rosell R, Riess JW, Doebele RC, Bivona TG
(2015) Nat Med 21: 1038-47
MeSH Terms: Anaplastic Lymphoma Kinase, Cell Line, Tumor, Drug Resistance, Neoplasm, Dual Specificity Phosphatase 6, Humans, Lung Neoplasms, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Oncogene Proteins, Fusion, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Receptor Protein-Tyrosine Kinases, ras Proteins
Show Abstract · Added January 26, 2016
One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.
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13 MeSH Terms
CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation.
Bertaux-Skeirik N, Feng R, Schumacher MA, Li J, Mahe MM, Engevik AC, Javier JE, Peek RM, Ottemann K, Orian-Rousseau V, Boivin GP, Helmrath MA, Zavros Y
(2015) PLoS Pathog 11: e1004663
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Cell Proliferation, Disease Models, Animal, Epithelial Cells, Gastric Fundus, Gastric Mucosa, Gene Deletion, Helicobacter Infections, Helicobacter pylori, Humans, Hyaluronan Receptors, Mice, Receptor Protein-Tyrosine Kinases
Show Abstract · Added March 28, 2016
The cytotoxin-associated gene (Cag) pathogenicity island is a strain-specific constituent of Helicobacter pylori (H. pylori) that augments cancer risk. CagA translocates into the cytoplasm where it stimulates cell signaling through the interaction with tyrosine kinase c-Met receptor, leading cellular proliferation. Identified as a potential gastric stem cell marker, cluster-of-differentiation (CD) CD44 also acts as a co-receptor for c-Met, but whether it plays a functional role in H. pylori-induced epithelial proliferation is unknown. We tested the hypothesis that CD44 plays a functional role in H. pylori-induced epithelial cell proliferation. To assay changes in gastric epithelial cell proliferation in relation to the direct interaction with H. pylori, human- and mouse-derived gastric organoids were infected with the G27 H. pylori strain or a mutant G27 strain bearing cagA deletion (∆CagA::cat). Epithelial proliferation was quantified by EdU immunostaining. Phosphorylation of c-Met was analyzed by immunoprecipitation followed by Western blot analysis for expression of CD44 and CagA. H. pylori infection of both mouse- and human-derived gastric organoids induced epithelial proliferation that correlated with c-Met phosphorylation. CagA and CD44 co-immunoprecipitated with phosphorylated c-Met. The formation of this complex did not occur in organoids infected with ∆CagA::cat. Epithelial proliferation in response to H. pylori infection was lost in infected organoids derived from CD44-deficient mouse stomachs. Human-derived fundic gastric organoids exhibited an induction in proliferation when infected with H. pylori that was not seen in organoids pre-treated with a peptide inhibitor specific to CD44. In the well-established Mongolian gerbil model of gastric cancer, animals treated with CD44 peptide inhibitor Pep1, resulted in the inhibition of H. pylori-induced proliferation and associated atrophic gastritis. The current study reports a unique approach to study H. pylori interaction with the human gastric epithelium. Here, we show that CD44 plays a functional role in H. pylori-induced epithelial cell proliferation.
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Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery.
Kothiwale S, Borza CM, Lowe EW, Pozzi A, Meiler J
(2015) Drug Discov Today 20: 255-61
MeSH Terms: Animals, Discoidin Domain Receptors, Drug Discovery, Humans, Molecular Structure, Protein Kinase Inhibitors, Protein Structure, Tertiary, Receptor Protein-Tyrosine Kinases, Receptors, Mitogen
Show Abstract · Added October 27, 2014
Discoidin domain receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of receptor tyrosine kinases (RTK). Upon collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, proliferation, differentiation, migration, and matrix homeostasis. Altered DDR function resulting from either mutations or overexpression has been implicated in several types of disease, including atherosclerosis, inflammation, cancer, and tissue fibrosis. Several established inhibitors, such as imatinib, dasatinib, and nilotinib, originally developed as Abelson murine leukemia (Abl) kinase inhibitors, have been found to inhibit DDR kinase activity. As we review here, recent discoveries of novel inhibitors and their co-crystal structure with the DDR1 kinase domain have made structure-based drug discovery for DDR1 amenable.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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