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tyrosine kinase inhibitor

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https://www.readbyqxmd.com/read/28731495/significance-of-neutrophil-to-lymphocyte-ratio-in-western-advanced-egfr-mutated-non-small-cell-lung-cancer-receiving-a-targeted-therapy
#1
Fausto Meriggi, Claudio Codignola, Giordano D Beretta, Giovanni L Ceresoli, Alberto Caprioli, Mario Scartozzi, Anna P Fraccon, Tiziana Prochilo, Chiara Ogliosi, Alberto Zaniboni
PURPOSE: Lung cancer is one of the leading causes of cancer-related death worldwide and, although targeted therapy with tyrosine kinase inhibitors has dramatically improved the rates of response and survival in advanced EGFR-mutated adenocarcinoma, the overall outcome remains unsatisfactory. Therefore, new prognostic factors, preferably simple, inexpensive, and easy to reproduce on a large scale, are needed. We performed a retrospective analysis of our database including 63 western Caucasian patients with advanced EGFR-mutated lung adenocarcinoma and receiving gefitinib, erlotinib, or afatinib as first- or second-line therapy...
July 14, 2017: Tumori
https://www.readbyqxmd.com/read/28730963/increased-expression-of-ire1%C3%AE-associates-with-the-resistant-mechanism-of-osimertinib-azd9291-resistant-non-small-cell-lung-cancer-hcc827-osir-cells
#2
Zheng-Hai Tang, Min-Xia Su, Xia Guo, Xiao-Ming Jiang, Lin Jia, Xiuping Chen, Jin-Jian Lu
BACKGROUND: Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients. OBJECTIVE: Establishment of the OSI-resistant HCC827/OSIR cell line and study of its resistant mechanism. METHOD: The anti-proliferative effect was studied through MTT and colony formation assays. The protein expression was detected by Western blot assay...
July 19, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28730960/protein-kinases-as-tumor-biomarkers-and-therapeutic-targets
#3
Chuntao Quan, Juanjuan Xiao, Lin Liu, Qiuhong Duan, Ping Yuan, Feng Zhu
Over the last three decades, neoplasms have become the largest cause of human mortality due to both high tumor incidence and mortality. Chemotherapy is one of the main therapies employed to treat neoplasms. Although classical genotoxic drugs, such as cyclophosphamide, 5-FU, cisplatin and doxorubicin have been applied in clinical settings and have achieved very good treatment efficacy, many cancer patients died of tumor metastasis, drug toxicity or drug resistance due to tumor heterogeneity. Targeted molecular treatments based on the genes, receptors, and kinases expressed by a tumor make individualized treatment possible...
July 20, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28730479/analysis-of-drug-resistance-using-kinome-wide-functional-screens
#4
Katherine R Singleton, Keith T Earley, Lynn E Heasley
The clinical success of tyrosine kinase inhibitors specific for BCR-ABL-, EGFR-, ALK-, and ROS1-driven cancers continues to spur the quest to match specific oncogene-defined tumor types with an appropriate molecularly targeted therapy. Unfortunately, responses to these agents are not durable with intrinsic or acquired resistance limiting benefit. Additionally, efforts to identify the appropriate targets of new drugs have focused on nonfunctional assays such as large-scale sequencing for somatic mutations or analysis of gene copy number...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28730474/allosteric-modulation-of-src-family-kinases-with-atp-competitive-inhibitors
#5
Ames C Register, Sujata Chakraborty, Dustin J Maly
The Src family kinases (SFKs) are an important family of tyrosine kinases that are allosterically regulated by their SH2 and SH3 domains. Engagement of SFK SH2 and SH3 domains with their intramolecular ligands leads to reduced kinase activity by stabilizing an inactive ATP-binding site conformation. Disruption of these intramolecular interactions stabilizes a more active ATP-binding site conformation and restores SFK activity. Interestingly, this allosteric relationship is bidirectional in that ATP-competitive ligands that stabilize distinct active site conformations can divergently modulate the abilities of the regulatory SH2 and SH3 domains to participate in intermolecular interactions...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28730290/a-phase-i-study-to-investigate-the-metabolism-excretion-and-pharmacokinetics-of-14-c-fruquintinib-a-novel-oral-selective-vegfr-inhibitor-in-healthy-chinese-male-volunteers
#6
Sufeng Zhou, Feng Shao, Zhaoqiang Xu, Lu Wang, Ke Jin, Lijun Xie, Juan Chen, Yun Liu, Hongwen Zhang, Ning Ou
PURPOSE: Fruquintinib (HMPL-013) is a novel, potent, and highly selective tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors (1, 2 and 3). This study was conducted to investigate the metabolism, excretion, and pharmacokinetics of HMPL-013 after a single oral dose to healthy Chinese men. METHODS: Six subjects were administrated an oral suspension containing 5 mg of (14)C-labeled HMPL-013 (100 μCi) in a fasted state. Blood and excreta samples were collected at the designated time points or intervals for pharmacokinetics and radiometric analyses...
July 20, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28729437/estradiol-induced-regulation-of-glut4-in-3t3-l1-cells-involvement-of-esr1-and-akt-activation
#7
Raquel Campello, Luciana Fátima, João Barreto-Andrade, Thais Fg Lucas, Rosana Cristina Tieko Mori, Catarina Segreti Porto, Ubiratan Fabres Machado
Impaired insulin-stimulated glucose uptake involves reduced expression of the GLUT4 (solute carrier family 2 facilitated glucose transporter member 4, SLC2A4 gene). 17β-estradiol (E2) modulates SLC2A4/GLUT4 expression, but the involved mechanisms are unclear. Although E2 exerts its biological effects by binding to estrogen receptors 1/2 (ESR1/2), which are nuclear transcriptional factors; extranuclear effects have also been proposed. We hypothesize that E2 regulates GLUT4 through a mechanism related to extranuclear ESR1...
July 20, 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28729403/autophagy-inhibition-improves-sunitinib-efficacy-in-pancreatic-neuroendocrine-tumors-via-a-lysosome-dependent-mechanism
#8
Tabea Wiedmer, Annika Blank, Sophia Pantasis, Lea Normand, Ruben Bill, Philippe Krebs, Mario P Tschan, Ilaria Marinoni, Aurel Perren
Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNETs) is an unmet medical need. The anti-angiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. Additionally, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28729178/elevated-cardiovascular-disease-risk-in-patients-with-chronic-myelogenous-leukemia-seen-in-community-based-oncology-practices-in-the-united-states
#9
Anna D Coutinho, Dinara Makenbaeva, Eileen Farrelly, Pamela B Landsman-Blumberg, Daniel Lenihan
INTRODUCTION: Current National Comprehensive Cancer Network guidelines recommend that comorbidities, including cardiovascular disease (CVD), be considered when selecting tyrosine kinase inhibitors for the treatment of chronic myelogenous leukemia (CML). We report here the prevalence of CVD and its risk factors in patients with CML treated by community-based United States (US) oncologists. PATIENTS AND METHODS: Adult patients with a confirmed diagnosis of CML and ≥ 1 encounter after the first date of CML diagnosis in an electronic medical record database between January 1, 2005 and October 31, 2014 were enrolled...
June 17, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28728751/a-phase-ii-evaluation-of-brivanib-in-the-treatment-of-persistent-or-recurrent-carcinoma-of-the-cervix-an-nrg-oncology-gynecologic-oncology-group-study
#10
John K Chan, Wei Deng, Robert V Higgins, Krishnansu S Tewari, Albert J Bonebrake, Michael Hicks, Stephanie Gaillard, Pedro T Ramirez, Weldon Chafe, Bradley J Monk, Carol Aghajanian
BACKGROUND: Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. METHODS: Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity...
July 17, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28727840/dual-inhibition-of-fes-and-flt3-tyrosine-kinases-potently-inhibits-flt3-itd-aml-cell-growth
#11
Mark C Weir, Sabine Hellwig, Li Tan, Yao Liu, Nathanael S Gray, Thomas E Smithgall
Acute myelogenous leukemia (AML) is often associated with activating mutations in the receptor tyrosine kinase, Flt3, including internal tandem duplications (ITDs) within the regulatory juxtamembrane region. Previous studies have linked Flt3-ITD to the activation of the Fes protein tyrosine kinase in AML, and RNAi-knockdown studies suggest that Fes may be required for Flt3 function. In this study, we tested Fes inhibitors from three different chemical classes for their growth-suppressive activity against Flt3-ITD+ myeloid leukemia cell lines (MV4-11, MOLM-13 and MOLM-14) vs...
2017: PloS One
https://www.readbyqxmd.com/read/28727830/the-receptor-tyrosine-kinase-axl-promotes-migration-and-invasion-in-colorectal-cancer
#12
Diana J Uribe, Edward K Mandell, Adam Watson, Jesse D Martinez, Jonathan A Leighton, Sourav Ghosh, Carla V Rothlin
The receptor tyrosine kinases (RTKs) TYRO3, AXL and MERTK (TAM) have well-described oncogenic functions in a number of cancers. Notwithstanding, TAM RTKs are also potent and indispensable inhibitors of inflammation. The combined deletion of Axl and Mertk in mice enhances chronic inflammation and autoimmunity, including increased inflammation in the gut and colitis-associated cancer. On the other hand, deletion of Tyro3 increases the risk of allergic responses. Therefore, the indiscriminate inhibition of these TAM RTKs could result in undesirable immunological diseases...
2017: PloS One
https://www.readbyqxmd.com/read/28726812/a-patient-with-germ-line-gain-of-function-pdgfrb-p-n666h-mutation-and-marked-clinical-response-to-imatinib
#13
Dinel Pond, Florence A Arts, Nancy J Mendelsohn, Jean-Baptiste Demoulin, Gunter Scharer, Yoav Messinger
PurposeHeterozygous germ-line activating mutations in PDGFRB cause Kosaki and Penttinen syndromes and myofibromatosis. We describe a 10-year-old child with a germ-line PDGFRB p.N666H mutation who responded to the tyrosine kinase inhibitor imatinib by inhibition of PDGFRB.MethodsThe impact of p.N666H on PDGFRB function and sensitivity to imatinib was studied in cell culture.ResultsCells expressing the p.N666H mutation showed constitutive PDGFRB tyrosine phosphorylation. PDGF-independent proliferation was abolished by imatinib at 1 μM concentration...
July 20, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28726562/gene-therapy-for-age-related-macular-degeneration
#14
Nicholas A Moore, Peter Bracha, Rehan M Hussain, Nuria Morral, Thomas A Ciulla
In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes associated with 'real world' undertreatment. Areas covered: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-associated virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD...
July 20, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28725539/the-evolving-treatment-landscape-of-advanced-renal-cell-carcinoma-in-patients-progressing-after-vegf-inhibition
#15
REVIEW
Pedro C Barata, Moshe C Ornstein, Jorge A Garcia
Despite significant changes in the therapeutic landscape of renal cell carcinoma, the majority of patients with metastatic disease eventually progress after first-line treatment with vascular endothelial growth factor receptors (VEGFR) tyrosine kinase inhibitor (TKI) therapy. Understanding existing data on subsequent therapies is crucial to define an optimal treatment sequence following first-line failure. This review examines the data supporting currently approved agents in this setting and provides a framework for decision-making regarding treatment sequencing beyond first-line therapy with VEGFR TKIs...
2017: Journal of Kidney Cancer and VHL
https://www.readbyqxmd.com/read/28724911/honokiol-inhibits-c-met-ho-1-tumor-promoting-pathway-and-its-cross-talk-with-calcineurin-inhibitor-mediated-renal-cancer-growth
#16
Murugabaskar Balan, Samik Chakraborty, Evelyn Flynn, David Zurakowski, Soumitro Pal
Honokiol (HNK) is a small molecule with potent anti-inflammatory and anti-tumorigenic properties; yet the molecular targets of HNK are not well studied. Hyperactivation of the receptor tyrosine kinase c-Met and overexpression of the cytoprotective enzyme heme oxygenase-1 (HO-1) play a critical role in the growth and progression of renal cell carcinoma (RCC). Interestingly, the calcineurin inhibitor (CNI) cyclosporine A (CsA), an immunosuppressant used to prevent allograft rejection, can also increase the risk of RCC in transplant patients...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28724631/the-axl-kinase-domain-in-complex-with-a-macrocyclic-inhibitor-offers-first-structural-insights-into-an-active-tam-receptor-kinase
#17
Ketan S Gajiwala, Neil Grodsky, Ben Bolaños, Junli Feng, RoseAnn Ferre, Sergei Timofeevski, Meirong Xu, Brion W Murray, Ted W Johnson, Al Stewart
The receptor tyrosine kinase (RTK) family consisting of Tyro3, Axl and Mer (TAM) is one of the most recently identified RTK families. TAM receptors are upregulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination...
July 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28724615/glioblastoma-cellular-cross-talk-converges-on-nf-%C3%AE%C2%BAb-to-attenuate-egfr-inhibitor-sensitivity
#18
Ciro Zanca, Genaro R Villa, Jorge A Benitez, Amy Haseley Thorne, Tomoyuki Koga, Matteo D'Antonio, Shiro Ikegami, Jianhui Ma, Antonia D Boyer, Afsheen Banisadr, Nathan M Jameson, Alison D Parisian, Olesja V Eliseeva, Gabriela F Barnabe, Feng Liu, Sihan Wu, Huijun Yang, Jill Wykosky, Kelly A Frazer, Vladislav V Verkhusha, Maria G Isaguliants, William A Weiss, Timothy C Gahman, Andrew K Shiau, Clark C Chen, Paul S Mischel, Webster K Cavenee, Frank B Furnari
In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs)...
July 19, 2017: Genes & Development
https://www.readbyqxmd.com/read/28723866/a-case-of-resistance-to-tyrosine-kinase-inhibitor-therapy-small-cell-carcinoma-transformation-concomitant-with-plasma-genotyped-t790m-positivity
#19
Yanjun Xu, Zhiyu Huang, Lei Gong, Yun Fan
Although non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitors, drug resistances are always inevitable. The secondary somatic EGFR threonine-methionine substitution at position 790 (T790M) mutation accounts for ∼50% of acquired resistance mechanisms. Small cell lung cancer (SCLC) transformation is a relatively rare mechanism, but has recently attracted considerable attention. The coexistence of both the mechanisms in one patient is much more scarce in clinic...
July 18, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28723342/molecular-analysis-of-circulating-free-dna-from-lung-cancer-patients-in-routine-laboratory-practice-a-cross-platform-comparison-of-three-different-molecular-methods-for-mutation-detection
#20
Stephan Bartels, Sascha Persing, Britta Hasemeier, Elisa Schipper, Hans Kreipe, Ulrich Lehmann
Cell-free DNA (cfDNA), which is isolated from blood plasma, represents a noninvasive source for the detection of mutations conferring resistance against epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small-cell lung cancer patients. In advanced disease stages, performing regular biopsies is often not possible because of the general health condition of the patients. Furthermore, a biopsy of a single tumor lesion or metastasis may not reflect the heterogeneous genotype of the tumor and its metastases...
July 16, 2017: Journal of Molecular Diagnostics: JMD
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