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Receptor tyrosine kinase

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https://www.readbyqxmd.com/read/29793020/epha2-stimulates-vcam-1-expression-through-calcium-dependent-nfat1-activity
#1
Steven Daniel Funk, Alexandra C Finney, Arif Yurdagul, Christopher B Pattillo, A Wayne Orr
Endothelial cell activation by proinflammatory stimuli drives leukocyte recruitment through enhanced expression of counter-receptors such as vascular cell adhesion molecule-1 (VCAM-1). We previously demonstrated that activation of the receptor tyrosine kinase EphA2 with its ligand ephrin-A1 induces VCAM-1 expression. Here, we sought to characterize the proinflammatory signaling pathways involved. Analysis of over-represented transcription factors in ephrin-A1-induced genes identified multiple potential transcriptional regulators, including the Rel family members nuclear factor-κB (NF-κB/p65) and nuclear factor of activated T-cells (NFAT)...
May 21, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29792724/a-systematic-understanding-of-signaling-by-erbb2-in-cancer-using-phosphoproteomics
#2
C Sidhanth, P Manasa, S Krishnapriya, S Sneha, S Bindhya, R P Nagare, M Garg, T S Ganesan
ErbB2 is an important receptor tyrosine kinase and a member of the ErbB family. Although it does not have a specific ligand, it transmits signals downstream by heterodimerization with other receptors in the family. It plays a major role in a variety of cellular responses like proliferation, differentiation, and adhesion. ErbB2 is amplified at the DNA level in breast cancer (20%-30%) and gastric cancer (10%-20%), and trastuzumab is effective as a therapeutic antibody. This review is a critical analysis of the currently published data on the signaling pathways of ErbB2 and the interacting proteins...
May 24, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/29792386/disparate-effects-of-shb-gene-deficiency-on-disease-characteristics-in-murine-models-of-myeloid-b-cell-and-t-cell-leukemia
#3
Maria Jamalpour, Xiujuan Li, Karin Gustafsson, Jeffrey W Tyner, Michael Welsh
The Src homology-2 domain protein B is an adaptor protein operating downstream of tyrosine kinases. The Shb gene knockout has been found to accelerate p210 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced leukemia. In human myeloid leukemia were tumors with high Src homology-2 domain protein B mRNA content, tumors were, however, associated with decreased latency and myeloid leukemia exhibiting immune cell characteristics. Thus, the aim of this study was to investigate the effects of Shb knockout on the development of leukemia in three additional models, that is, colony stimulating factor 3 receptor-T618I-induced neutrophilic leukemia, p190 Breakpoint cluster region-cAbl oncogene 1 tyrosine kinase-induced B-cell leukemia, and G12D-Kras-induced T-cell leukemia/thymic lymphoma...
April 2018: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/29792310/bet-inhibition-overcomes-receptor-tyrosine-kinase-mediated-cetuximab-resistance-in-hnscc
#4
Brandon Leonard, Toni M Brand, Rachel A O'Keefe, Eliot Lee, Yan Zang, Jacquelyn D Kemmer, Hua Li, Jennifer R Grandis, Neil E Bhola
Cetuximab, the FDA-approved anti-EGFR antibody for head and neck squamous cell carcinoma (HNSCC), has displayed limited efficacy due to the emergence of intrinsic and acquired resistance. We and others have demonstrated that cetuximab resistance in HNSCC is driven by alternative receptor tyrosine kinases (RTK) including HER3, MET, and AXL. In an effort to overcome cetuximab resistance and circumvent toxicities associated with the administration of multiple RTK inhibitors, we sought to identify a common molecular target that regulates expression of multiple RTK...
May 23, 2018: Cancer Research
https://www.readbyqxmd.com/read/29792121/abcg2-polymorphism-rs2231142-and-hypothyroidism-in-metastatic-renal-cell-carcinoma-patients-treated-with-sunitinib
#5
Emilie Werbrouck, Julie Bastin, Diether Lambrechts, Annelies Verbiest, Thomas Van Brussel, Evelyne Lerut, Jean-Pascal Machiels, Vincent Verschaeve, Vincent Richard, Philip R Debruyne, Brigitte Decallonne, Patrick Schöffski, Oliver Bechter, Pascal Wolter, Benoit Beuselinck
Background and aim Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) cause significant adverse events including thyroid dysfunction, mainly hypothyroidism, in a considerable proportion of patients. In a series of metastatic renal cell carcinoma (mRCC) patients treated with sunitinib, we aimed to study the correlation between hypothyroidism and single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics and pharmacodynamics. Patients and methods We included 79 mRCC patients who started sunitinib between November 2005 and March 2016...
May 23, 2018: Acta Clinica Belgica
https://www.readbyqxmd.com/read/29790264/immune-responses-against-tumor-associated-antigen-derived-cytotoxic-t-lymphocyte-epitopes-in-cholangiocarcinoma-patients
#6
Akihiko Kida, Eishiro Mizukoshi, Toshikatsu Tamai, Takeshi Terashima, Masaaki Kitahara, Kuniaki Arai, Tatsuya Yamashita, Kazumi Fushimi, Masao Honda, Shuichi Kaneko
BACKGROUND & AIMS: Immunotherapy is a promising treatment option for cholangiocarcinoma. We compared cytotoxic T lymphocyte (CTL) responses against several tumor-associated antigen (TAA)-derived epitopes in cholangiocarcinoma patients to identify candidate epitopes for immunotherapy. METHODS: Twenty-six TAAs were selected, and the expression of TAAs in 6 cholangiocarcinoma cell lines and 9 specimens were measured using real-time polymerase chain reaction (PCR)...
May 23, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29790151/irreversible-modifications-of-receptor-tyrosine-kinases
#7
Matthew Kreitman, Ashish Noronha, Yosef Yarden
Each group of the 56 receptor tyrosine kinases (RTK) binds with one or more soluble growth factors and coordinates a vast array of cellular functions. These outcomes are tightly regulated by inducible post-translational events, such as tyrosine phosphorylation, ubiquitination, ectodomain shedding and regulated intramembrane proteolysis. Because of the delicate balance required for appropriate RTK function, cells may become pathogenic upon dysregulation of RTKs themselves or their post-translational covalent modifications...
May 22, 2018: FEBS Letters
https://www.readbyqxmd.com/read/29789423/atp-binding-cassette-member-b5-abcb5-promotes-tumor-cell-invasiveness-in-human-colorectal-cancer
#8
Qin Guo, Tanja Grimmig, Gabriel Gonzalez, Anita Giobbie-Hurder, Gretchen Berg, Nolan Carr, Brian J Wilson, Pallavi Banerjee, Jie Ma, Jason S Gold, Bisweswar Nandi, Qin Huang, Ana Maria Waaga-Gasser, Christine G Lian, George F Murphy, Markus H Frank, Martin Gasser, Natasha Y Frank
ATP-binding cassette member B5 (ABCB5) mediates multidrug resistance (MDR) in diverse malignancies and confers clinically relevant 5-fluorouracil resistance to CD133-expressing cancer stem cells (CSCs) in human colorectal cancer (CRC). Because of its recently identified roles in normal stem cell maintenance, we hypothesized that ABCB5 might also serve MDR-independent functions in CRC. Here, in a prospective clinical study of 142 CRC patients, we found that ABCB5 mRNA transcripts previously reported not to be significantly expressed in healthy peripheral blood mononuclear cells are significantly enriched in patient peripheral blood specimens compared with non-CRC controls and correlate with CRC disease progression...
May 22, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29789418/juxtacrine-signaling-inhibits-antitumor-immunity-by-upregulating-pd-l1-expression
#9
Wen-Hao Yang, Jong-Ho Cha, Weiya Xia, Heng-Huan Lee, Li-Chuan Chan, Ying-Nai Wang, Jennifer L Hsu, Guoxin Ren, Mien-Chie Hung
Programmed death-ligand 1 (PD-L1) is a well-known immune checkpoint protein that helps cancer cells evade immune response. Anti-PD-L1 immune therapy has been approved for the treatment of several advanced human cancers. Therefore, further understanding of the regulatory mechanisms of PD-L1 is critical to improve PD-L1-targeting immunotherapy. Recent studies indicated that contact-dependent pathways may regulate anticancer immunity, highlighting the importance of cell contact-induced signaling in cancer immunity...
May 22, 2018: Cancer Research
https://www.readbyqxmd.com/read/29789296/tuning-itam-multiplicity-on-t-cell-receptors-can-control-potency-and-selectivity-to-ligand-density
#10
John R James
The T cell antigen receptor (TCR) recognizes peptides from pathogenic proteins bound in the major histocompatibility complex (MHC). To convert this binding event into downstream signaling, the TCR complex contains immunoreceptor tyrosine-based activation motifs (ITAMs) that act as docking sites for the cytoplasmic tyrosine kinase ZAP-70. Unique among antigen receptors, the TCR complex uses 10 ITAMs to transduce peptide-MHC binding to the cell interior. Using synthetic, drug-inducible receptor-ligand pairs, it was found that greater ITAM multiplicity primarily enhanced the efficiency with which ligand binding was converted into an intracellular signal...
May 22, 2018: Science Signaling
https://www.readbyqxmd.com/read/29789220/adaura-phase-iii-double-blind-randomized-study-of-osimertinib-versus-placebo-in-egfr-mutation-positive-early-stage-nsclc-after-complete-surgical-resection
#11
Yi-Long Wu, Roy S Herbst, Helen Mann, Yuri Rukazenkov, Marcelo Marotti, Masahiro Tsuboi
INTRODUCTION: Currently, the role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as adjuvant therapy for early-stage non-small-cell lung cancer after complete surgical tumor resection remains under investigation. We present the rationale and study design for the ADAURA (ClinicalTrials.gov identifier, NCT02511106) trial, a multicenter, double-blind, randomized, placebo-controlled study. PATIENTS AND METHODS: Study entry will be limited to adults aged ≥ 18 years (and in Japan and Taiwan, age ≥ 20 years) with primary nonsquamous stage IB-IIIA non-small-cell lung cancer with central confirmation of an EGFR exon 19 deletion or L858R mutation...
May 1, 2018: Clinical Lung Cancer
https://www.readbyqxmd.com/read/29789021/epidermal-growth-factor-receptor-egfr-t790m-mutation-identified-in-plasma-indicates-failure-sites-and-predicts-clinical-prognosis-in-non-small-cell-lung-cancer-progression-during-first-generation-tyrosine-kinase-inhibitor-therapy-a-prospective-observational
#12
Shirong Zhang, Lucheng Zhu, Bing Xia, Enguo Chen, Qiong Zhao, Xiaochen Zhang, Xueqin Chen, Xufeng Chen, Shenglin Ma
INTRODUCTION: Plasma circulating tumor DNA (ctDNA) is an ideal approach to detecting the epidermal growth factor receptor (EGFR) T790M mutation, which is a major mechanism of resistance to first-generation EGFR-tyrosine kinase inhibitor (TKI) therapy. The present study aimed to explore the association of ctDNA-identified T790M mutation with disease failure sites and clinical prognosis in non-small cell lung cancer (NSCLC) patients. METHODS: Patients who progressed on first-generation TKIs were categorized into failure site groups of chest limited (CF), brain limited (BF) and other (OF)...
May 22, 2018: Cancer communications
https://www.readbyqxmd.com/read/29787706/circuit-wiring-neurite-speed-dating-versus-stable-synaptic-matchmaking
#13
Heike Blockus, Franck Polleux
Understanding the mechanisms establishing the complex but precise pattern of connectivity characterizing neural circuits remains an immense challenge. In a recent issue of Neuron, Mao and colleagues (2018) provide new insights by showing that the activation kinetics of EphB2, a transmembrane receptor tyrosine kinase, control whether dendritic filopodia makes a synapse with candidate axons.
May 21, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29787268/bisphosphonate-generated-atp-analogs-inhibit-cell-signaling-pathways
#14
Satish R Malwal, Bing O'Dowd, Xinxin Feng, Petri A Turhanen, Christopher J Shin, Jiaqi Yao, Boo Kyung Kim, Noman Baig, Tianhui Zhou, Sandhya Bansal, Rahul L Khade, Yong Zhang, Eric Oldfield
Bisphosphonates are a major class of drugs used to treat osteoporosis, Paget's disease, and cancer. They have been pro-posed to act by inhibiting one more targets including protein prenylation; the epidermal growth factor receptor; or the adenine nucleotide translocase. Inhibition of the latter is due to formation in cells of analogs of ATP: the isopentenyl ester of ATP (ApppI) or an AppXp-type analog of ATP, such as AMP-clodronate (AppCCl2p). We screened both ApppI as well as AppCCl2p against a panel of 369 kinases finding potent inhibition of some tyrosine kinases by AppCCl2p, attributable to formation of a strong hydrogen bond between tyrosine and the terminal phosphonate...
May 22, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29786782/preclinical-impact-of-high-dose-intermittent-antiangiogenic-tyrosine-kinase-inhibitor-pazopanib-in-intrinsically-resistant-tumor-models
#15
Elaine Reguera-Nuñez, Shan Man, Ping Xu, Robert S Kerbel
Antiangiogenic tyrosine kinase inhibitors (TKIs) target vascular endothelial growth factor receptors and other receptor tyrosine kinases. As a result of toxicity, the clinical failures or the modest benefits associated with antiangiogenic TKI therapy may be related in some cases to suboptimal drug dosing and scheduling, thereby facilitating resistance. Most antiangiogenic TKIs, including pazopanib, are administered on a continuous daily basis. Here, instead, we evaluated the impact of increasing the dose and administering the drug intermittently...
May 21, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29786108/mir%C3%A2-494-inhibits-cancer%C3%A2-initiating-cell-phenotypes-and-reverses-resistance-to-lapatinib-by-downregulating-fgfr2-in-her2%C3%A2-positive-gastric-cancer
#16
Yanxia Yu, Xuejuan Yu, Hong Liu, Qingxun Song, Yongmei Yang
In gastric cancer, >15% of cases are associated with the amplification of human epidermal growth factor receptor 2 (HER2), which leads to poor clinical outcomes. Lapatinib, a potent ATP‑competitive inhibitor, is a small, orally active molecule, which inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1. The activation of receptor tyrosine kinases can contribute to lapatinib resistance in HER2‑positive gastric cancer. The aim of the present study was to explore the effects of miR‑494 and FGFR2 in regulation of cancer‑initiating cell phenotypes and therapeutic efficiency of lapatinib in HER2‑positive gastric cancer...
May 16, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29785010/genome-wide-analyses-identify-68-new-loci-associated-with-intraocular-pressure-and-improve-risk-prediction-for-primary-open-angle-glaucoma
#17
Anthony P Khawaja, Jessica N Cooke Bailey, Nicholas J Wareham, Robert A Scott, Mark Simcoe, Robert P Igo, Yeunjoo E Song, Robert Wojciechowski, Ching-Yu Cheng, Peng T Khaw, Louis R Pasquale, Jonathan L Haines, Paul J Foster, Janey L Wiggs, Chris J Hammond, Pirro G Hysi
Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4 . Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP...
May 21, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29784788/mistimed-food-intake-and-sleep-alters-24-hour-time-of-day-patterns-of-the-human-plasma-proteome
#18
Christopher M Depner, Edward L Melanson, Andrew W McHill, Kenneth P Wright
Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i...
May 21, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29784748/emerging-treatment-options-for-acute-lymphoblastic-leukemia-focus-on-car-t-cell-therapy
#19
Patrick A Brown, Bijal Shah
Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of diseases with different morphologic, cytogenetic, and molecular subgroups, some of which have significant therapeutic implications. It typically presents with an aggressive clinical course, and among adults, responds poorly to standard chemotherapy, and carries a high risk for relapse. Despite the significant progress made in inducing remission, frequent relapses remain a challenge. Novel drugs, such as potent later-generation tyrosine kinase inhibitors, antibody-drug conjugates, bispecific monoclonal antibodies, and chimeric antigen receptor (CAR) T-cell therapies, are being investigated in patients with ALL...
May 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29784046/knockdown-of-annexin-a5-restores-gefitinib-sensitivity-by-promoting-g2-m-cell-cycle-arrest
#20
Jian Zhou, Meijia Chang, Jing Li, Tao Fang, Jie Hu, Chunxue Bai
BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, including gefitinib, are first-line drugs against advanced non-small cell lung cancer with activating EGFR mutations. However, the development of resistance to such drugs is a major clinical challenge. METHODS: The role of annexin A5 in resistance to EGFR tyrosine kinase inhibitors was investigated by qPCR and western blot of relevant molecules, by CCK8 and EdU assay of cell proliferation and viability, by annexin V/propidium iodide assay of apoptosis and cell cycle distribution, by JC-1 assay of mitochondrial integrity, and by xenograft assay of tumorigenicity...
May 21, 2018: Respiratory Research
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