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https://www.readbyqxmd.com/read/29164492/advanced-melanoma-current-treatment-options-biomarkers-and-future-perspectives
#1
REVIEW
Elisa A Rozeman, Tim J A Dekker, John B A G Haanen, Christian U Blank
Malignant melanoma accounts for the highest number of deaths from skin cancer, and the prognosis of patients with stage IV disease has historically been poor. Novel insights into both mutations driving tumorigenesis and immune escape mechanisms of these tumors have led to effective treatment options that have revolutionized the treatment of this disease. Targeting the MAPK kinase pathway (with BRAF and MEK inhibitors), as well as targeting checkpoints, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or programmed death 1 (PD-1), have improved overall survival in patients with late-stage melanoma, and biomarker research for personalized therapy is ongoing for each of these treatment modalities...
November 21, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/29162825/outcomes-of-patients-with-sarcoma-enrolled-in-clinical-trials-of-pazopanib-combined-with-histone-deacetylase-mtor-her2-or-mek-inhibitors
#2
Vikas Dembla, Roman Groisberg, Ken Hess, Siqing Fu, Jennifer Wheler, David S Hong, Filip Janku, Ralph Zinner, Sarina Anne Piha-Paul, Vinod Ravi, Robert S Benjamin, Shreyaskumar Patel, Neeta Somaiah, Cynthia E Herzog, Daniel D Karp, Jason Roszik, Funda Meric-Bernstam, Vivek Subbiah
Pazopanib is US FDA approved for the treatment of advanced soft tissue sarcomas. All patients with this disease ultimately develop resistance to therapy. Mechanisms of resistance include activation of the mTOR, histone deacetylase (HDAC), MAPK, and ERBB4 pathways. We hypothesized that combining pazopanib with other targeted agents inhibiting these pathways would increase response rates. We retrospectively evaluated the safety and efficacy of pazopanib plus vorinostat, everolimus, lapatinib or trastuzumab, and MEK inhibitor in patients with advanced sarcoma...
November 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29161237/bilateral-visual-field-defects-in-a-patient-treated-with-the-mek-and-braf-inhibitors-trametinib-and-dabrafenib-for-melanoma-of-unknown-origin
#3
Jakob Siedlecki, Marc Mackert, Armin Wolf, Carola Berking, Siegfried G Priglinger, Kirsten Eibl-Lindner
INTRODUCTION: Although the introduction of BRAF and MEK inhibitors has greatly enhanced treatment possibilities in advanced BRAFV600-mutated melanoma, class-related toxicities are rather frequent and often involve the eye. Ophthalmologic side effects most commonly include central/diffuse serous retinopathy and retinal vein occlusion. Affection of the optic nerve head however has not been described clinically. CASE REPORT: A 29-year-old man presented in our eye clinic with bilateral blurred vision...
April 17, 2017: Retinal Cases & Brief Reports
https://www.readbyqxmd.com/read/29160857/synergistic-effects-of-danshen-salvia-miltiorrhizae-radix-et-rhizoma-and-sanqi-notoginseng-radix-et-rhizoma-combination-in-angiogenesis-behavior-in-eahy-926-cells
#4
Xian Zhou, Valentina Razmovski-Naumovski, Antony Kam, Dennis Chang, Chunguang Li, Alan Bensoussan, Kelvin Chan
Background: This study investigated the combination effects of the Danshen and Sanqi herb pair on angiogenesis in vitro. Methods: Nine combination ratios of Danshen-Sanqi extracts (DS-SQ) were screened for their angiogenic effects in the human vascular endothelial EAhy 926 cell line via cell proliferation, cell migration and tube formation activities against the damage to the cells exerted by DL-homocysteine (Hcy) and adenosine (Ado). The type of interaction (synergistic, antagonistic, additive) between Danshen and Sanqi was analyzed using combination index (CI) and isobologram models...
November 21, 2017: Medicines (Basel, Switzerland)
https://www.readbyqxmd.com/read/29160030/dihydromyricetin-enhances-glucose-uptake-by-inhibition-of-mek-erk-pathway-and-consequent-down-regulation-of-phosphorylation-of-ppar%C3%AE-in-3t3-l1-cells
#5
Lei Liu, Min Zhou, Hedong Lang, Yong Zhou, Mantian Mi
Accumulating evidence suggests that inhibition of mitogen-activated protein kinase signalling can reduce phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at serine 273, which mitigates obesity-associated insulin resistance and might be a promising treatment for type 2 diabetes. Dihydromyricetin (DHM) is a flavonoid that has many beneficial pharmacological properties. In this study, mouse fibroblast 3T3-L1 cells were used to investigate whether DHM alleviates insulin resistance by inhibiting PPARγ phosphorylation at serine 273 via the MEK/ERK pathway...
November 21, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29159332/a-biomaterial-screening-approach-reveals-microenvironmental-mechanisms-of-drug-resistance
#6
Alyssa D Schwartz, Lauren E Barney, Lauren E Jansen, Thuy V Nguyen, Christopher L Hall, Aaron S Meyer, Shelly R Peyton
Traditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell-cell contacts act independently or are integrated within a cell to affect either drug sensitivity or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment...
November 21, 2017: Integrative Biology: Quantitative Biosciences From Nano to Macro
https://www.readbyqxmd.com/read/29157819/pro-angiogenic-effects-of-ilexsaponin-a1-on-human-umbilical-vein-endothelial-cells-in-vitro-and-zebrafish-in-vivo
#7
Jingjing Li, Jinming Zhang, Liang Zou, Simon Ming-Yuen Lee, Cui Yang, Sai-Wang Seto, George Pak-Heng Leung
BACKGROUND: Ilexsaponin A1 is the major bioactive ingredient of Ilex pubescens Hook. et Arn. This plant has been conventionally used in Traditional Chinese Medicine for the treatment of cardiovascular diseases including stroke, coronary arterial disease, and peripheral vascular diseases. PURPOSE: To investigate the pro-angiogenic effect of Ilexsaponin A1 and its mechanism of action. STUDY DESIGN: Human umbilical vein endothelial cells (HUVECs) and transgenic zebrafish Tg(fli1:EGFP) were employed as an in vitro and in vivo model respectively...
December 1, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29156708/a-preclinical-evaluation-of-the-mek-inhibitor-refametinib-in-her2-positive-breast-cancer-cell-lines-including-those-with-acquired-resistance-to-trastuzumab-or-lapatinib
#8
John O'Shea, Mattia Cremona, Clare Morgan, Malgorzata Milewska, Frankie Holmes, Virginia Espina, Lance Liotta, Joyce O'Shaughnessy, Sinead Toomey, Stephen F Madden, Aoife Carr, Naomi Elster, Bryan T Hennessy, Alex J Eustace
Purpose: The MEK/MAPK pathway is commonly activated in HER2-positive breast cancer, but little investigation of targeting this pathway has been undertaken. Here we present the results of an in vitro preclinical evaluation of refametinib, an allosteric MEK1/2 inhibitor, in HER2-positive breast cancer cell lines including models of acquired resistance to trastuzumab or lapatinib. Methods: A panel of HER2-positive breast cancer cells were profiled for mutational status and also for anti-proliferative response to refametinib alone and in combination with the PI3K inhibitor (PI3Ki) copanlisib and the HER2-targeted therapies trastuzumab and lapatinib...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156677/overcoming-resistance-to-single-agent-therapy-for-oncogenic-braf-gene-fusions-via-combinatorial-targeting-of-mapk-and-pi3k-mtor-signaling-pathways
#9
Payal Jain, Amanda Silva, Harry J Han, Shih-Shan Lang, Yuankun Zhu, Katie Boucher, Tiffany E Smith, Aesha Vakil, Patrick Diviney, Namrata Choudhari, Pichai Raman, Christine M Busch, Tim Delaney, Xiaodong Yang, Aleksandra K Olow, Sabine Mueller, Daphne Haas-Kogan, Elizabeth Fox, Phillip B Storm, Adam C Resnick, Angela J Waanders
Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156488/association-of-pd-l1-expression-with-treatment-outcomes-in-patients-with-braf-mutation-positive-melanoma-treated-with-vemurafenib-or-cobimetinib-combined-with-vemurafenib
#10
Matthew J Wongchenko, Antoni Ribas, Brigitte Dréno, Paolo A Ascierto, Grant A McArthur, Jorge D Gallo, Isabelle A Rooney, Jessie Hsu, Hartmut Koeppen, Yibing Yan, James Larkin
The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1(+) melanoma, with hazard ratios (HRs) (PD-L1(+) versus PD-L1(-) ) of 0...
November 20, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29155323/the-role-of-p2x7r-erk-signaling-in-dorsal-root-ganglia-satellite-glial-cells-in-the-development-of-chronic-postsurgical-pain-induced-by-skin-muscle-incision-and-retraction-smir
#11
Jingnian Song, Yanlu Ying, Wei Wang, Xianguo Liu, Xuebing Xu, Xuhong Wei, Xiangcai Ruan
The mechanisms of chronic postsurgical pain remain to be elucidated.. We reported here that skin/muscle incision and retraction (SMIR), a rat model of postsurgical pain, phosphorylated the extracellular regulated protein kinases (ERK) signaling components c-Raf, MEK (ERK kinase) and ERK1/2 in lumbar 3 dorsal root ganglion (L3 DRG) in rats. Intrathecal injection of ERK specific inhibitor SCH772984 suppressed the mechanical allodynia induced by SMIR. Further more, SMIR upregulated tumor necrosis factor alpha (TNFα) in L3 DRG, which could be inhibited by SCH772984...
November 16, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29154827/secretogranin-iii-promotes-angiogenesis-through-mek-erk-signaling-pathway
#12
Fen Tang, Mario Thiego F Pacheco, Ping Chen, Dan Liang, Wei Li
Secretogranin III (Scg3) was recently discovered as the first highly diabetic retinopathy-associated angiogenic factor, and its neutralizing antibody alleviated the disease with high efficacy in diabetic mice. Investigation of its molecular mechanisms will facilitate the translation of this novel therapy. Scg3 was reported to induce the phosphorylation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). Here we characterized the importance of MEK/ERK activation to Scg3 angiogenic activity...
November 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29152126/extracellular-atp-as-an-energy-and-phosphorylating-molecule-induces-different-types-of-drug-resistances-in-cancer-cells-through-atp-internalization-and-intracellular-atp-level-increase
#13
Xuan Wang, Yunsheng Li, Yanrong Qian, Yanyang Cao, Pratik Shriwas, Haiyun Zhang, Xiaozhuo Chen
Cancer cells are able to uptake extracellular ATP (eATP) via macropinocytosis to elevate intracellular ATP (iATP) levels, enhancing their survival in drug treatment. However, the involved drug resistance mechanisms are unknown. Here we investigated the roles of eATP as either an energy or a phosphorylating molecule in general drug resistance mediated by ATP internalization and iATP elevation. We report that eATP increased iATP levels and promoted drug resistance to various tyrosine kinase inhibitors (TKIs) and chemo-drugs in human cancer cell lines of five cancer types...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29152067/propoxur-enhances-mmp-2-expression-and-the-corresponding-invasion-of-human-breast-cancer-cells-via-the-erk-nrf2-signaling-pathway
#14
Yunxiang Shi, Daizhi An, Yiping Liu, Qiong Feng, Xu Fang, Guilan Pan, Qiang Wang
Propoxur is considered a prime etiological suspect of increasing tumor incidence, but the role is still undefined. In this study, two human breast cancer cells lines, MCF-7 and MDA-MB-231 cells, were used as cell models. Cells were respectively treated with 0, 0.01, 1, or 100 μM propoxur. PD98059, a MEK inhibitor, was administered to block the ERK/MAPK pathway. Migration and reactive oxygen species were measured by wound healing and Transwell assays, and flow cytometry. Protein expression and subcellular location were detected by western blotting and immunofluorescence staining, respectively...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29150975/downregulation-of-dusp4-enhances-cell-proliferation-and-invasiveness-in-colorectal-carcinomas
#15
Michihiro Ichimanda, Naoki Hijiya, Yoshiyuki Tsukamoto, Tomohisa Uchida, Chisato Nakada, Tomonori Akagi, Tsuyoshi Etoh, Hidekatsu Iha, Masafumi Inomata, Mutsuhiro Takekawa, Masatsugu Moriyama
It is widely accepted that aberrant activation of the Wnt signaling pathway is responsible for the development of precursor lesions of colorectal cancer (CRC). However, the molecular mechanisms involved in the process of progression from these precursor lesions to invasive lesions of CRC are not fully understood. Recently, we reported that constitutive activation of MAPK accompanied by downregulation of dual-specificity phosphatase 4 (DUSP4), a MAPK phosphatase, contributes to the progression of precursor lesions in the pancreas...
November 18, 2017: Cancer Science
https://www.readbyqxmd.com/read/29149136/mapk-pathway-targeted-therapies-care-and-management-of-unique-toxicities-in-patients-with-advanced-melanoma%C3%A2
#16
Krista M Rubin
BACKGROUND: Agents targeting the MAPK pathway, including inhibitors of BRAF and MEK, have dramatically transformed the treatment landscape for patients with BRAF-mutant metastatic melanoma. Although generally well tolerated, targeted agents were associated with unique toxicities.
. OBJECTIVES: This article aims to provide nurses with an overview of the key toxicities and associated management strategies of the characteristic adverse event (AE) profile associated with agents targeting the MAPK pathway...
December 1, 2017: Clinical Journal of Oncology Nursing
https://www.readbyqxmd.com/read/29148538/molecular-testing-for-braf-mutations-to-inform-melanoma-treatment-decisions-a-move-toward-precision-medicine
#17
Liang Cheng, Antonio Lopez-Beltran, Francesco Massari, Gregory T MacLennan, Rodolfo Montironi
Approximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation. Targeted therapy with BRAF and MEK inhibitors is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma. Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy. A literature search was performed using MEDLINE/PubMed and scientific congress databases using the terms 'BRAF,' 'mutation,' and 'cancer/tumor...
November 17, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29146887/targeted-therapy-of-gastroenteropancreatic-neuroendocrine-tumours-preclinical-strategies-and-future-targets
#18
Elke Tatjana Aristizabal Prada, Christoph J Auernhammer
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mTOR-inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression free survival due to tumor resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP-system are needed. This paper reviews preclinical research models and signaling pathways in NETs of the GEP-system...
November 16, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/29141923/src-family-kinase-inhibitors-blunt-the-pacap-induced-pac1-receptor-endocytosis-phosphorylation-of-erk-and-increase-in-cardiac-neuron-excitability
#19
John D Tompkins, Todd A Clason, Thomas R Buttolph, Beatrice M Girard, Anne K Linden, Jean C Hardwick, Laura A Merriam, Victor May, Rodney L Parsons
Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) activation of PAC1 receptors (Adcyap1r1) significantly increases excitability of guinea pig cardiac neurons. This modulation of excitability is mediated in part by plasma membrane G protein-dependent activation of adenylyl cyclase and downstream signaling cascades. However, additional mechanisms responsible for the enhanced excitability are activated following internalization of the PAC1 receptor and endosomal signaling. Src family kinases play critical roles mediating endocytosis of many trophic factor and G-protein coupled receptors...
November 15, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29140794/targeted-elimination-of-senescent-ras-transformed-cells-by-suppression-of-mek-erk-pathway
#20
Elena Y Kochetkova, Galina I Blinova, Olga A Bystrova, Marina G Martynova, Valery A Pospelov, Tatiana V Pospelova
The Ras-Raf-MEK-ERK pathway plays a central role in tumorigenesis and is a target for anticancer therapy. The successful strategy based on the activation of cell death in Ras-expressing cells is associated with the suppression of kinases involved in Ras pathway. However, activation of cytoprotective autophagy overcomes antiproliferative effect of the inhibitors and develops drug resistance. We studied whether cellular senescence induced by HDAC inhibitor sodium butyrate in E1a+cHa-Ras-transformed rat embryo fibroblasts (ERas) and A549 human Ki-Ras mutated lung adenocarcinoma cells would enhance the tumor suppressor effect of MEK/ERK inhibition...
November 14, 2017: Aging
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