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https://www.readbyqxmd.com/read/28654888/mek-inhibition-enhances-efficacy-of-bacillus-calmette-gu%C3%A3-rin-on-bladder-cancer-cells-by-reducing-release-of-toll-like-receptor-2-activated-antimicrobial-peptides
#1
Young Mi Whang, Su Bin Jin, Serk In Park, In Ho Chang
Bacillus Calmette-Guérin (BCG) is one of the standard treatment options for non-muscle-invasive bladder cancer. The details of the biological defense mechanisms against BCG remain unclear. Here, we investigated whether BCG-induced release of antimicrobial peptides (AMPs; e.g., human β-defensin-2, -3, and cathelicidin) is involved with mitogen-activated protein kinase (MAPK) pathways, and investigated the enhanced anticancer effect of BCG through the down-regulation of Toll-like receptors (TLRs) and MAPK pathways in bladder cancer cells...
May 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28649441/clinical-responses-to-erk-inhibition-in-braf-v600e-mutant-colorectal-cancer-predicted-using-a-computational-model
#2
Daniel C Kirouac, Gabriele Schaefer, Jocelyn Chan, Mark Merchant, Christine Orr, Shih-Min A Huang, John Moffat, Lichuan Liu, Kapil Gadkar, Saroja Ramanujan
Approximately 10% of colorectal cancers harbor BRAF(V600E) mutations, which constitutively activate the MAPK signaling pathway. We sought to determine whether ERK inhibitor (GDC-0994)-containing regimens may be of clinical benefit to these patients based on data from in vitro (cell line) and in vivo (cell- and patient-derived xenograft) studies of cetuximab (EGFR), vemurafenib (BRAF), cobimetinib (MEK), and GDC-0994 (ERK) combinations. Preclinical data was used to develop a mechanism-based computational model linking cell surface receptor (EGFR) activation, the MAPK signaling pathway, and tumor growth...
2017: NPJ Systems Biology and Applications
https://www.readbyqxmd.com/read/28648698/three-year-pooled-analysis-of-factors-associated-with-clinical-outcomes-across-dabrafenib-and-trametinib-combination-therapy-phase-3-randomised-trials
#3
Dirk Schadendorf, Georgina V Long, Daniil Stroiakovski, Boguslawa Karaszewska, Axel Hauschild, Evgeny Levchenko, Vanna Chiarion-Sileni, Jacob Schachter, Claus Garbe, Caroline Dutriaux, Helen Gogas, Mario Mandalà, John B A G Haanen, Céleste Lebbé, Andrzej Mackiewicz, Piotr Rutkowski, Jean-Jacques Grob, Paul Nathan, Antoni Ribas, Michael A Davies, Ying Zhang, Mathilde Kaper, Bijoyesh Mookerjee, Jeffrey J Legos, Keith T Flaherty, Caroline Robert
AIM: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit...
June 21, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28646893/clinical-features-of-serous-retinopathy-observed-with-cobimetinib-in-patients-with-braf-mutated-melanoma-treated-in-the-randomized-cobrim-study
#4
Luis de la Cruz-Merino, Lorenza Di Guardo, Jean-Jacques Grob, Alfredo Venosa, James Larkin, Grant A McArthur, Antoni Ribas, Paolo A Ascierto, Jeffrey T R Evans, Antonio Gomez-Escobar, Giulio Barteselli, Susan Eng, Jessie J Hsu, Anne Uyei, Brigitte Dréno
BACKGROUND: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF (V600)-mutated melanoma treated in the Phase III coBRIM study. METHODS: In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed...
June 24, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28646880/6-shogaol-a-neuroactive-compound-of-ginger-jahe-gajah-induced-neuritogenic-activity-via-ngf-responsive-pathways-in-pc-12-cells
#5
Syntyche Ling Sing Seow, Sok Lai Hong, Guan Serm Lee, Sri Nurestri Abd Malek, Vikineswary Sabaratnam
BACKGROUND: Ginger is a popular spice and food preservative. The rhizomes of the common ginger have been used as traditional medicine to treat various ailments. 6-Shogaol, a pungent compound isolated from the rhizomes of jahe gajah (Zingiber officinale var officinale) has shown numerous pharmacological activities, including neuroprotective and anti-neuroinflammatory activities. The aim of this study was to investigate the potential of 6-shogaol to mimic the neuritogenic activity of nerve growth factor (NGF) in rat pheochromocytoma (PC-12) cells...
June 24, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28641665/-research-progress-of-ras-raf-mek-erk-signaling-pathways-in-leukemia-review
#6
Jing Liu, Na Lv, Yong-Hui Li, Li Yu
Ras/Raf/MEK/ERK signaling pathway plays an important role in the occurrence and development of leukemia. Using the inhibitors of key signaling components in the signaling pathway is new strategy for the treatment of leukemia. In recent years, the screening of these inhibitors and their in vitro and in vivo researches have become a hot spot in the field of treatment. In vivo and in vitro experiments and early clinical studies have shown that these inhibitors have good effect and application prospects in the treatment of leukemia...
June 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28640105/glomerulonephritis-and-granulomatous-vasculitis-in-kidney-as-a-complication-of-the-use-of-braf-and-mek-inhibitors-in-the-treatment-of-metastatic-melanoma-a-case-report
#7
Mehdi Maanaoui, Camille Saint-Jacques, Viviane Gnemmi, Marie Frimat, Arnaud Lionet, Marc Hazzan, Christian Noël, François Provot
RATIONALE: BRAF and MEK inhibitors have significantly improved the prognosis of metastatic melanoma, by inhibiting both the mitogen-activated protein kinase (MAP-kinase) pathway. They are associated with infrequent adverse kidney events. Most of these are related to the use of BRAF inhibitors and involve interstitial nephritis with acute tubular necrosis. PATIENT CONCERNS: We report a unique case of glomerulonephritis with renal granulomatous vasculitis in a patient diagnosed with metastatic melanoma treated with BRAF and MEK inhibitors...
June 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28637716/modulation-of-plasma-metabolite-biomarkers-of-mapk-pathway-with-the-mek-inhibitor-ro4987655-pharmacodynamic-and-predictive-potential-in-metastatic-melanoma
#8
Joo Ern Ang, Akos Pal, Yasmin J Asad, Alan T Henley, Melanie Valenti, Gary Box, Alexis de Haven Brandon, Victoria Revell, Debra J Skene, Miro Venturi, Ruediger Rueger, Valerie Meresse, Suzanne A Eccles, Johann S de Bono, Stanley B Kaye, Paul Workman, Udai Banerji, Florence I Raynaud
<p>MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines and sphingomyelins that were significantly altered in two B-RAF mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655...
June 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28636555/overcoming-resistance-to-targeted-therapy-with-immunotherapy-and-combination-therapy-for-metastatic-melanoma
#9
REVIEW
Hilary R Keller, Xin Zhang, Li Li, Helmut Schaider, James W Wells
Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease...
June 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28634084/drug-delivery-to-melanoma-brain-metastases-can-current-challenges-lead-to-new-opportunities
#10
Gautham Gampa, Shruthi Vaidhyanathan, Jann N Sarkaria, William F Elmquist
Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease...
June 17, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28633868/daidzein-stimulates-osteogenesis-facilitating-proliferation-differentiation-and-antiapoptosis-in-human-osteoblast-like-mg-63-cells-via-estrogen-receptor-dependent-mek-erk-and-pi3k-akt-activation
#11
Xin Jin, Jing Sun, Bo Yu, Yue Wang, Wei Jia Sun, Jing Yang, Su Hui Huang, Wen Li Xie
Daidzein, a natural soy isoflavone, has a structure similar to estradiol and exhibiting bone-sparing effects against osteoporosis. However, the molecular mechanisms of osteogenesis remain unclear. We hypothesized that daidzein stimulates osteogenesis through estrogen receptor (ER)-dependent signal pathways. To test this hypothesis, we investigated the effects of daidzein compared with 17β-estradiol on proliferation, differentiation, and cisplatin-induced apoptosis in human osteoblast-like MG-63 cells containing 2 ER isoforms...
June 2017: Nutrition Research
https://www.readbyqxmd.com/read/28632938/mek-inhibitors-induce-akt-activation-and-drug-resistance-by-suppressing-negative-feedback-erk-mediated-her2-phosphorylation-at-thr701
#12
Chia-Hung Chen, Te-Chun Hsia, Ming-Hsin Yeh, Tsung-Wei Chen, Yun-Ju Chen, Jung-Tsu Chen, Ya-Ling Wei, Chih-Yen Tu, Wei-Chien Huang
Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2-positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase-dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event...
June 20, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28631187/serine-peptidase-inhibitor-kazal-type-1-spink1-as-novel-downstream-effector-of-the-cadherin-17-%C3%AE-catenin-axis-in-hepatocellular-carcinoma
#13
Felix H Shek, Ruibang Luo, Brian Y H Lam, Wing Kin Sung, Tak-Wah Lam, John M Luk, Ming Sum Leung, Kin Tak Chan, Hector K Wang, Chung Man Chan, Ronnie T Poon, Nikki P Lee
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Previously, we reported that cadherin-17 (CDH17) and its related CDH17/β-catenin axis may be responsible for inducing HCC in a subset of patients exhibiting CDH17 over-expression. Here we aimed at obtaining a better understanding of the CDH17-related HCC biology and to obtain further indications for the design of targeted therapies in CDH17 over-expressing HCC patients. RESULTS: We found that SPINK1 acts as a downstream effector of the CDH17/β-catenin axis in HCC...
June 19, 2017: Cellular Oncology (Dordrecht)
https://www.readbyqxmd.com/read/28630054/slc45a2-a-melanoma-antigen-with-high-tumor-selectivity-and-reduced-potential-for-autoimmune-toxicity
#14
Jungsun Park, Amjad H Talukder, Seonah Lim, Kwanghee Kim, Ke Pan, Brenda Melendez, Sherille D Bradley, Kyle Jackson, Jahan S Khalili, Junmei Wang, Caitlin Creasy, Bih-Fang Pan, Scott E Woodman, Chantale Bernatchez, David Hawke, Patrick Hwu, Kyung-Mi Lee, Jason Roszik, Gregory Lizee, Cassian Yee
Cytotoxic T lymphocyte (CTL)-based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma.  Although the melanocyte differentiation antigens (MDAs) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets...
June 19, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28629184/determination-of-structural-requirements-of-n-substituted-tetrahydro-%C3%AE-carboline-imidazolium-salt-derivatives-using-in-silico-approaches-for-designing-mek-1-inhibitors
#15
Jingwei Liang, Mingyang Wang, Xinyang Li, Xin He, Chong Cao, Fanhao Meng
Novel N-substituted tetrahydro-β-carboline imidazolium salt derivatives proved to have potent antitumor activity in past research. The Topomer CoMFA and CoMSIA function in Sybyl-X 2.0 software was applied for the identification of important features of N-substituted tetrahydro-β-carboline-imidazolium salt derivative moieties. In the case of Topomer CoMFA, all the compounds were split into two fragments which were used to generate a 3D invariant representation, the statistical results of the Topomer CoMFA model: q² value of 0...
June 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28628649/insights-into-the-binding-mode-of-mek-type-iii-inhibitors-a-step-towards-discovering-and-designing-allosteric-kinase-inhibitors-across-the-human-kinome
#16
Zheng Zhao, Lei Xie, Philip E Bourne
Protein kinases are critical drug targets for treating a large variety of human diseases. Type-III kinase inhibitors have attracted increasing attention as highly selective therapeutics. Thus, understanding the binding mechanism of existing type-III kinase inhibitors provides useful insights into designing new type-III kinase inhibitors. In this work, we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28627617/sorafenib-controls-the-epithelial%C3%A2-mesenchymal-transition-of-ovarian-cancer-cells-via-egf-and-the-cd44%C3%A2-ha-signaling-pathway-in-a-cell-type%C3%A2-dependent-manner
#17
Ga Bin Park, Hyun-Suk Ko, Daejin Kim
Cluster of differentiation (CD) 44 and epidermal growth factor (EGF) are closely involved in cellular migration and have been used as stem cell markers. Although the hyaluronan (HA)‑binding CD44 is responsible for enhanced cellular motility, the mechanism underlying its actions in various cell types and clinical conditions have yet to be elucidated. In the present study, the multikinase inhibitor sorafenib was used to investigate the diverse effects of EGF stimulation on epithelial‑mesenchymal transition (EMT) in ovarian cancer cells using immunoblotting and reverse transcription‑polymerase chain reaction...
June 14, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28623774/discrepancy-in-braf-status-among-patients-with-metastatic-malignant-melanoma-a-meta-analysis
#18
REVIEW
Antonis Valachis, Gustav J Ullenhag
The incidence of malignant melanoma is growing rapidly. Approximately half of the cases are BRAF mutated, making treatment with kinase inhibitors a (MEK and BRAF inhibitors) preferred choice in the advanced setting. The vast majority of these patients will benefit from the treatment. It is therefore of vital importance that the BRAF analysis is reliable and reflects the true nature of the tumour. Intraindividual tumour BRAF heterogeneity may exist, and changes of BRAF status over time might occur. We reviewed the literature by searching the PubMed database and 630 potentially relevant studies were identified...
June 14, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28622036/molecular-targeted-drugs-and-treatment-of-colorectal-cancer-recent-progress-and-future-perspectives
#19
Fang Geng, Zheng Wang, Hang Yin, Junxian Yu, Bangwei Cao
Nowadays, colorectal cancer is the fourth most common type of tumor all over the world. When diagnosed, ∼50%-60% of tumors have metastasized, thus resulting in a grim prognosis. Chemotherapy is regarded as standard treatment for patients with colorectal cancer, however, limitations of chemotherapy cannot be ignored, such as low selectivity, insufficient concentrations in tumor tissues, and systemic toxicity. Recently, six targeted drugs have been approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic colorectal cancer (mCRC), including bevacizumab, aflibercept, regorafenib, cetuximab, and panitumumab...
June 2017: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28621502/amniotic-membrane-stimulates-cell-migration-by-modulating-transforming-growth-factor-%C3%AE-signaling
#20
Catalina Ruiz-Cañada, Ángel Bernabé-García, Sergio Liarte, Carmen Luisa Insausti, Diego Angosto, José María Moraleda, Gregorio Castellanos, Francisco José Nicolás
Keratinocyte migration is a mandatory aspect of wound-healing. We have previously shown that Amniotic Membrane (AM) applied to chronic wounds assists healing through a process resulting in overexpression of c-Jun at the wound's leading edge. Also, we have demonstrated that amniotic membrane modifies the genetic program induced by TGF-ß in chronic wounds. In this paper, we used a scratch assay of Mv1Lu and HaCaT cells to examine the influence of AM application on the underlying signaling during scratch closure...
June 16, 2017: Journal of Tissue Engineering and Regenerative Medicine
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