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https://www.readbyqxmd.com/read/29050366/the-resistance-mechanisms-and-treatment-strategies-for-egfr-mutant-advanced-non-small-cell-lung-cancer
#1
REVIEW
Wen-Zhao Zhong, Qing Zhou, Yi-Long Wu
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been established as the standard therapy for EGFR-sensitizing mutant advanced non-small-cell lung cancer (NSCLC). However, patients ultimately develop resistance to these drugs. There are several mechanisms of both primary and secondary resistance to EGFR-TKIs. The primary resistance mechanisms include point mutations in exon 18, deletions or insertions in exon 19, insertions, duplications and point mutations in exon 20 and point mutation in exon 21 of EGFR gene...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050327/prognostic-and-predictive-value-of-serum-carcinoembryonic-antigen-levels-in-advanced-non-small-cell-lung-cancer-patients-with-epidermal-growth-factor-receptor-sensitive-mutations-and-receiving-tyrosine-kinase-inhibitors
#2
Xin Min Zhao, Jing Zhao, Kai Lin Xing, Si Sun, Zhi Guo Luo, Hui Jie Wang, Jia Lei Wang, Jian Hua Chang, Xiang Hua Wu
BACKGROUND: Despite the widespread use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced or recurrent non-small cell lung cancer (NSCLC), no biomarkers for predicting the efficacy of EGFR-TKIs in patients with EGFR-sensitive mutations have yet been identified. The purpose of our study was to explore the effect of baseline serum tumor markers in stage IIIB/IV NSCLC patients treated with EGFR-TKIs. METHODS: One hundred and seventy-seven patients with stage IIIB/IV NSCLC who harbored EGFR-sensitive mutations and were treated with EGFR-TKIs were retrospectively reviewed...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050315/the-activation-of-src-family-kinases-and-focal-adhesion-kinase-with-the-loss-of-the-amplified-mutated-egfr-gene-contributes-to-the-resistance-to-afatinib-erlotinib-and-osimertinib-in-human-lung-cancer-cells
#3
Yuichi Murakami, Kahori Sonoda, Hideyuki Abe, Kosuke Watari, Daiki Kusakabe, Koichi Azuma, Akihiko Kawahara, Jun Akiba, Chitose Oneyama, Jonathan A Pachter, Kazuko Sakai, Kazuto Nishio, Michihiko Kuwano, Mayumi Ono
Second- and third-generation inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity (EGFR-TKIs) are improving the treatment of patients with non-small cell lung cancer. Here we established two sublines (BR1-8 and BR2-3) resistant to a second-generation inhibitor, afatinib, from the human lung cancer cell line HCC827 that harbors a mutation that activates the tyrosine kinase activity of EGFR. These afatinib-resistant sublines were resistant to first-generation EGFR-TKIs, gefitinib and erlotinib, and a third-generation EGFR-TKI, osimertinib...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050198/mtorc1-autophagy-regulated-mertk-in-mutant-brafv600-melanoma-with-acquired-resistance-to-braf-inhibition
#4
Gongda Xue, Reto Kohler, Fengyuan Tang, Debby Hynx, Yuhua Wang, Francesca Orso, Vincent Prêtre, Reto Ritschard, Petra Hirschmann, Peter Cron, Tim Roloff, Reinhard Dummer, Mario Mandalà, Sandrine Bichet, Christel Genoud, Alexandra G Meyer, Manuele G Muraro, Giulio C Spagnoli, Daniela Taverna, Curzio Rüegg, Taha Merghoub, Daniela Massi, Huifang Tang, Mitchell P Levesque, Stephan Dirnhofer, Alfred Zippelius, Brian A Hemmings, Andreas Wicki
BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#5
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
September 19, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29048652/activation-of-src-signaling-mediates-acquired-resistance-to-alk-inhibition-in-lung-cancer
#6
Ryohei Yoshida, Takaaki Sasaki, Yoshinori Minami, Yukiko Hibino, Shunsuke Okumura, Masatoshi Sado, Naoyuki Miyokawa, Satoshi Hayashi, Masahiro Kitada, Yoshinobu Ohsaki
Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines...
September 28, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29048432/silencing-fli-or-targeting-cd13-anpep-lead-to-dephosphorylation-of-epha2-a-mediator-of-braf-inhibitor-resistance-and-induce-growth-arrest-or-apoptosis-in-melanoma-cells
#7
Alireza Azimi, Rainer Tuominen, Fernanda Costa Svedman, Stefano Caramuta, Maria Pernemalm, Marianne Frostvik Stolt, Lena Kanter, Pedram Kharaziha, Janne Lehtiö, Carolina Hertzman Johansson, Veronica Höiom, Johan Hansson, Suzanne Egyhazi Brage
A majority of patients with BRAF-mutated metastatic melanoma respond to therapy with BRAF inhibitors (BRAFi), but relapses are common owing to acquired resistance. To unravel BRAFi resistance mechanisms we have performed gene expression and mass spectrometry based proteome profiling of the sensitive parental A375 BRAF V600E-mutated human melanoma cell line and of daughter cell lines with induced BRAFi resistance. Increased expression of two novel resistance candidates, aminopeptidase-N (CD13/ANPEP) and ETS transcription factor FLI1 was observed in the BRAFi-resistant daughter cell lines...
August 31, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29048128/how-i-manage-relapse-of-chronic-myeloid-leukaemia-after-stopping-tyrosine-kinase-inhibitor-therapy
#8
REVIEW
Delphine Rea, François-Xavier Mahon
During the last 10 years, clinical trials formally demonstrated that about 50% of patients with chronic phase (CP) chronic myeloid leukaemia (CML) who achieve and maintain deep molecular responses for a prolonged period of time during treatment with imatinib or new generation tyrosine kinase inhibitors (TKIs) may successfully stop their anti-leukaemic therapy. Based on the accumulated knowledge from abundant clinical trial experience, TKI discontinuation is becoming an important goal to achieve and is about to enter clinical practice...
October 19, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/29047397/tyrosine-kinase-4-is-involved-in-the-reproduction-of-the-platyhelminth-parasite-schistosoma-japonicum
#9
Han Ding, Fengchun Liu, Lulu Zhu, Fei Wu, Quan Liu, Siyu He, Wei Shao, Yinan Du, Cuiping Ren, Jijia Shen, Miao Liu
BACKGROUND: Schistosomiasis is one of the most common parasitic diseases affecting millions of humans and animals worldwide. Understanding the signal transduction pathways and the molecular basis of reproductive regulation in schistosomes is critically important for developing new strategies for preventing and treating these infections. Syk kinases regulate the proliferation, differentiation, morphogenesis, and survival of various types of cells and have been identified in invertebrates...
October 18, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/29047122/the-presence-of-philadelphia-chromosome-does-not-confer-poor-prognosis-in-adult-pre-b-acute-lymphoblastic-leukaemia-in-the-tyrosine-kinase-inhibitor-era-a-surveillance-epidemiology-and-end-results-database-analysis
#10
Igwe J Igwe, Dongyun Yang, Akil Merchant, Noah Merin, George Yaghmour, Kevin Kelly, Giridharan Ramsingh
The BCR-ABL1 fusion gene is caused by a translocation between chromosomes 9 and 22, resulting in an abnormal chromosome 22 (Philadelphia chromosome; Ph). Prior to the introduction of tyrosine kinase inhibitors (TKI), the presence of BCR-ABL1 conferred a poor prognosis in patients with acute lymphoblastic leukaemia (ALL). We compared the survival of Ph+ and Ph-ALL during the period when TKIs were universally available in the US for Ph+ALL, using a Surveillance, Epidemiology, and End Results (SEER) Database analysis...
October 18, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/29046997/membrane-perturbation-through-novel-cell-penetrating-peptides-influences-intracellular-accumulation-of-imatinib-mesylate-in-cml-cells
#11
Devdeep Mukherjee, Niloy Kundu, Lopamudra Chakravarty, Birendra Behera, Prantar Chakrabarti, Nilmoni Sarkar, Tapas Kumar Maiti
Chronic myeloid leukemia is a stem cell disease with the presence of Philadelphia chromosome generated through reciprocal translocation of chromosome 9 and 22. The use of first- and second-generation tyrosine kinase inhibitors has been successful to an extent. However, resistance against such drugs is an emerging problem. Apart from several drug-resistant mechanisms, drug influx/efflux ratio appears to be one of the key determinants of therapeutic outcomes. In addition, intracellular accumulation of drug critically depends on cell membrane fluidity and lipid raft dynamics...
October 18, 2017: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/29046475/evidence-for-mast-cells-contributing-to-neuromuscular-pathology-in-an-inherited-model-of-als
#12
Emiliano Trias, Sofía Ibarburu, Romina Barreto-Núñez, Valentina Varela, Ivan C Moura, Patrice Dubreuil, Olivier Hermine, Joseph S Beckman, Luis Barbeito
Evidence indicates that neuroinflammation contributes to motor neuron degeneration in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease leading to progressive muscular paralysis. However, it remains elusive whether inflammatory cells can interact with degenerating distal motor axons, influencing the progressive denervation of neuromuscular junctions (NMJs). By analyzing the muscle extensor digitorum longus (EDL) following paralysis onset in the SOD1G93A rat model, we have observed a massive infiltration and degranulation of mast cells, starting after paralysis onset and correlating with progressive NMJ denervation...
October 19, 2017: JCI Insight
https://www.readbyqxmd.com/read/29046393/-rac1-stimulated-macropinocytosis-enhances-g%C3%AE-%C3%AF-activation-of-pi3k%C3%AE
#13
Zahra Erami, Bassem D Khalil, Gilbert Salloum, Yanhua Yao, Jaclyn LoPiccolo, Aliaksei Shymanets, Bernd Nürnberg, Anne R Bresnick, Jonathan M Backer
Phosphoinositide 3-kinases (PI 3-kinases) are regulated by a diverse range of upstream activators, including receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs), and small GTPases from the Ras, Rho and Rab families. For the Class IA PI 3-kinase PI3Kβ, two mechanisms for GPCR-mediated regulation have been described: direct binding of Gβγ subunits to the C2-helical domain linker of p110β, and Dock180/Elmo1-mediated activation of Rac1, which binds to the Ras-Binding Domain of p110β. We now show that the integration of these dual pathways is unexpectedly complex...
October 18, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29046392/nutlin-3-plus-tanshinone-iia-exhibits-synergetic-anti-leukemia-effect-with-imatinib-by-reactivating-p53-and-inhibiting-akt-mtor-pathway-in-ph-all
#14
Yong Guo, Yi Li, Bing Xiang, Xiao-Ou Huang, Hong-Bing Ma, Fang-Fang Wang, Yu-Ping Gong
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL kinase. Recent efforts focused on the development of more potent tyrosine kinase inhibitors (TKI) that also inhibit mutant tyrosine kinases such as nilotinib and dasatinib. Although major advances in the treatment of this aggressive disease with potent inhibitors of the BCR/ABL kinases, patients in remission frequently relapse due to drug resistance possibly mediated, at least in part, by compensatory activation of growth-signaling pathways and protective feedback signaling of leukemia cells in response to TKI-treatment...
October 18, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29045907/reactive-neutrophil-responses-dependent-on-the-receptor-tyrosine-kinase-c-met-limit-cancer-immunotherapy
#15
Nicole Glodde, Tobias Bald, Debby van den Boorn-Konijnenberg, Kyohei Nakamura, Jake S O'Donnell, Sabrina Szczepanski, Maria Brandes, Sarah Eickhoff, Indrajit Das, Naveen Shridhar, Daniel Hinze, Meri Rogava, Tetje C van der Sluis, Janne J Ruotsalainen, Evelyn Gaffal, Jennifer Landsberg, Kerstin U Ludwig, Christoph Wilhelm, Monika Riek-Burchardt, Andreas J Müller, Christoffer Gebhardt, Richard A Scolyer, Georgina V Long, Viktor Janzen, Michele W L Teng, Wolfgang Kastenmüller, Massimiliano Mazzone, Mark J Smyth, Thomas Tüting, Michael Hölzel
Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies...
October 17, 2017: Immunity
https://www.readbyqxmd.com/read/29045271/rhabdomyosarcoma-cells-are-susceptible-to-cell-death-by-ldk378-alone-or-in-combination-with-sorafenib-independently-of-anaplastic-lymphoma-kinase-status
#16
Nadezda Dolgikh, Simone Fulda
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is often overexpressed in rhabdomyosarcoma (RMS). However, its oncogenic and functional role in RMS remains unclear. Therefore, we investigated the antitumor activity of LDK378 (ceritinib), a new second-generation ALK inhibitor approved for patients with ALK-positive non-small-cell lung cancers. Here, we report that LDK378 reduces cell viability and induces cell death in RMS cell lines at low micromolar IC50 concentrations irrespective of ALK expression levels or phosphorylation status...
November 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/29045250/clinical-decision-making-for-immunotherapy-in-metastatic-renal-cell-carcinoma
#17
Manuela Schmidinger
PURPOSE OF REVIEW: To review the treatment options in metastatic renal cell carcinoma (mRCC) in the light of new immunotherapy results. RECENT FINDINGS: Second-line treatment strategies for treatment of mRCC after progression on first-line VEGF-targeted therapy have recently undergone a major change. Treatment guidelines currently recommend the use of either nivolumab, a programmed cell death 1 (PD-1) inhibitor, or cabozantinib, an inhibitor of multiple receptor tyrosine kinases, as preferred choices...
October 17, 2017: Current Opinion in Urology
https://www.readbyqxmd.com/read/29045015/the-small-molecule-mertk-inhibitor-unc2025-decreases-platelet-activation-and-prevents-thrombosis
#18
Brian R Branchford, Timothy J Stalker, Luke Law, Gilbert Acevedo, Susan Sather, Christine Brzezinski, Katina M Wilson, Katherine Minson, Alisa B Lee-Sherick, Pavel Davizon-Castillo, Christopher Ng, Weihe Zhang, Keith B Neeves, Steven R Lentz, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Deborah DeRyckere, Lawrence F Brass, Douglas K Graham, Jorge A Di Paola
BACKGROUND: Gas6 signals through the TAM (TYRO-3, AXL, MERTK) receptor family mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIb β3 integrin. OBJECTIVE: Here we describe anti-thrombotic effects mediated by UNC2025, a small molecule MERTK tyrosine kinase inhibitor. METHODS: MERTK phosphorylation and downstream signaling were assessed by immunoblot. Light transmission aggregometry, flow cytometry, and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregate formation in vitro...
October 17, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29044514/ccdc6-the-identity-of-a-protein-known-to-be-partner-in-fusion
#19
REVIEW
Aniello Cerrato, Francesco Merolla, Francesco Morra, Angela Celetti
Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types...
October 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29044016/drug-induced-hypothyroidism
#20
Leonardo F L Rizzo, Daniela L Mana, Héctor A Serra
The thyroid axis is particularly prone to interactions with a wide variety of drugs, whose list increases year by year. Hypothyroidism is the most frequent consequence of drug-induced thyroid dysfunction. The main mechanisms involved in the development of primary hypothyroidism are: inhibition of the synthesis and/or release of thyroid hormones, immune mechanisms related to the use of interferon and other cytokines, and the induction of thyroiditis associated with the use of tyrosine kinase inhibitors and drugs blocking the receptors for vascular endothelial growth factor...
2017: Medicina
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