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https://www.readbyqxmd.com/read/29146887/targeted-therapy-of-gastroenteropancreatic-neuroendocrine-tumours-preclinical-strategies-and-future-targets
#1
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/29140794/targeted-elimination-of-senescent-ras-transformed-cells-by-suppression-of-mek-erk-pathway
#2
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
https://www.readbyqxmd.com/read/29129563/da-raf-a-dominant-negative-antagonist-of-the-ras-erk-pathway-is-a-putative-tumor-suppressor
#3
Emiri Kanno, Osamu Kawasaki, Kazuya Takahashi, Kazunori Takano, Takeshi Endo
Activating mutations of RAS genes, particularly KRAS, are detected with high frequency in human tumors. Mutated Ras proteins constitutively activate the ERK pathway (Raf-MEK-ERK phosphorylation cascade), leading to cellular transformation and tumorigenesis. DA-Raf1 (DA-Raf) is a splicing variant of A-Raf and contains the Ras-binding domain (RBD) but lacks the kinase domain. Accordingly, DA-Raf antagonizes the Ras-ERK pathway in a dominant-negative fashion and suppresses constitutively activated K-Ras-induced cellular transformation...
November 9, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/29113345/combined-targeting-of-raf-and-mek-synergistically-inhibits-tumorigenesis-in-triple-negative-breast-cancer-model-systems
#4
Teddy S Nagaria, Changnian Shi, Charles Leduc, Victoria Hoskin, Soma Sikdar, Waheed Sangrar, Peter A Greer
Aberrant Ras-MAPK signaling from receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), is a hallmark of triple negative breast cancer (TNBC); thus providing rationale for targeting the Ras-MAPK pathway. Components of this EGFR/HER2-Ras-Raf-Mek-Erk pathway were co-targeted in the MDA-MB-231 and MDA-MB-468 human TNBC cell lines, and in vitro effects on signaling and cytotoxicity, as well as in vivo effects on xenograft tumor growth and metastasis were assessed...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29107340/langerhans-cell-histiocytosis-a-neoplastic-disorder-driven-by-ras-erk-pathway-mutations
#5
REVIEW
Gary Tran, Thy N Huynh, Amy S Paller
Langerhans cell histiocytosis (LCH) is a disorder of myeloid neoplasia of dendritic cells that affects 1 in 200,000 children <15 years of age and even fewer adults. LCH presents with a spectrum of clinical manifestations. High-risk stratification is reserved for infiltration of blood, spleen, liver, and lungs. After decades of debate on the disease pathogenesis, a neoplastic mechanism is now favored on the basis of LCH cell clonality, rare cases of familial clustering, and recent evidence of mutations involving the Ras/Raf/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase) pathway in lesional biopsy specimens...
October 26, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/29101736/clinical-implications-of-nras-overexpression-in-resectable-pancreatic-adenocarcinoma-patients
#6
Javier Martinez-Useros, Weiyao Li, Tihomir Georgiev-Hristov, Maria J Fernandez-Aceñero, Aurea Borrero-Palacios, Nuria Perez, Angel Celdran, Jesus Garcia-Foncillas
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and its incidence is rising worldwide. Although survival can be improved by surgical resection, when detected at an early stage, this type of cancer is usually asymptomatic, and disease becomes only apparent after metastasis. Adjuvant treatment does not improve survival, thus after surgery there is a lack of predictive and prognosis biomarkers to predict treatment response and survival. The mitogen-activated protein-kinase and phosphoinositide 3-kinase signalling pathways play a crucial role in cancer development and progression...
November 3, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/29097117/dasatinib-synergizes-with-atra-to-trigger-granulocytic-differentiation-in-atra-resistant-acute-promyelocytic-leukemia-cell-lines-via-lyn-inhibition-mediated-activation-of-raf-1-mek-erk
#7
Ming Ding, Xiang-Qin Weng, Yan Sheng, Jing Wu, Cui Liang, Xun Cai
All-trans retinoic acid (ATRA) resistance has been a critical problem in acute promyelocytic leukemia (APL) relapsed patients. In this study, dasatinib synergized with ATRA to trigger differentiation in ATRA-resistant APL cell lines. The combined treatment activated RAF-1, MEK and ERK as well as enhanced ATRA-promoted up-regulation of the protein level of PU.1, C/EBPβ and C/EBPε. U0126 (MEK specific inhibitor) and sorafenib tosylate (RAF-1 specific inhibitor) suppressed the combined treatment-induced differentiation, ERK phosphorylation and the up-regulation of C/EBPs and PU...
October 30, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29075346/t-cell-leukemia-control-via-ras-raf-pathway-inhibition-with-peptides
#8
G Marin, H Bruzzoni-Giovanelli, G Schinella
RATIONALE: RAS-RAF-MEK-ERK pathway has been considered a promising target for anticancer therapy. However, tumor cells may develop resistance against such drugs via hyperactivation of N-Ras, which explains why novel therapeut-ic approaches. In this sense, the Institute Curie- Université Pierre et Marie Curie (Paris 6) designed peptides in order to disturb Ras/Raf interaction which showed pro-apoptotic properties. These peptides were patented as WO2015001045 A2 (PCT/EP2014/064243)5. OBJECTIVE: In order to check the anti-tumoral action of WO2015001045 A2 peptides in a very aggressive BALB/c mice spontaneous leukemia called LB, we performed the present study...
July 2017: Journal of Medicine and Life
https://www.readbyqxmd.com/read/29073728/hoxa3-promotes-tumor-growth-of-human-colon-cancer-through-activating-egfr-ras-raf-mek-erk-signaling-pathway
#9
Xianxiang Zhang, Guangwei Liu, Lei Ding, Tao Jiang, Shihong Shao, Yuan Gao, Yun Lu
Homeobox A3 (HOXA3), one of HOX transcription factors, regulates gene expression during embryonic development. HOXA3 expression has been reported to be associated with several cancers; however, its role in colon cancer and underlying mechanism are still unclear. The expression of HOXA3 in 232 paired of human colon tumor and adjacent non-tumorous tissues were measured by qPCR. The relationship between HOXA3 expression and clinical outcomes were analyzed by Kaplan-Meier survival curves analysis. Human colon cancer cell lines HT29 and HTC116 were transfected with HOXA3 siRNA or HOXA3 expressing vector, and then cell proliferation and apoptosis were assessed, respectively...
October 26, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29070145/-effect-of-erk1-2-signaling-pathway-inhibitor-pd98059-on-the-expression-of-ras-braf-mek-erk1-2-in-marrow-nucleated-red-blood-cells-of-cms-patients
#10
Yuan-Fang Han, Lin-Hua Ji, Ting-Ting Feng, Fang Liu, Sen Cui, Juan Su
OBJECTIVE: To investigate the effect of ERK1 / 2 signaling pathway inhibitor PD98059 on Ras, Raf, MEK, ERK1, ERK2 expression in order to explore a new way for basic research and clinical treatment of the chronic mountain sickness(CMS). METHODS: Sixteen CMS patients were selected, the bone marrow was collected for isolation of monomuclear cells (MNC), the cells were sorted by using CD71 and CD235a antibody magnetic beads, then positive cells were diveded into 5 groups: blank control, DMSO and PD98059 5, 10 and 20 µmol/L, and were cultured in hypoxid condition for 72 hours...
October 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29059211/screening-differential-mirnas-responsible-for-permeability-increase-in-huvecs-infected-with-influenza-a-virus
#11
Shujing Zhang, Ying Wu, Zinan Xuan, Xiaoming Chen, Junjie Zhang, Dongyu Ge, Xudan Wang
Severe influenza infections are featured by acute lung injury, a syndrome of increased pulmonary microvascular permeability. A growing number of evidences have shown that influenza A virus induces cytoskeletal rearrangement and permeability increase in endothelial cells. Although miRNA's involvement in the regulation of influenza virus infection and endothelial cell (EC) function has been well documented, little is known about the miRNA profiles in influenza-infected endothelial cells. Using human umbilical vein endothelial cells (HUVECs) as cell models, the present study aims to explore the differential miRNAs in influenza virus-infected ECs and analyze their target genes involved in EC permeability regulation...
2017: PloS One
https://www.readbyqxmd.com/read/29054855/h-ras-deletion-protects-against-angiotensin-ii-induced-arterial-hypertension-and-cardiac-remodeling-through-protein-kinase-g-i%C3%AE-pathway-activation
#12
Paloma Martín-Sánchez, Alicia Luengo, Mercedes Griera, María Jesús Orea, Marina López-Olañeta, Antonio Chiloeches, Enrique Lara-Pezzi, Sergio de Frutos, Manuel Rodríguez-Puyol, Laura Calleros, Diego Rodríguez-Puyol
Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs. We have demonstrated that H-ras gene deletion produces mice hypotension via a soluble guanylate cyclase-protein kinase G (PKG)-dependent mechanism. In this study, we analyzed the consequences of H-ras deletion on cardiac remodeling induced by continuous angiotensin II (AngII) infusion and the molecular mechanisms implied. Left ventricular posterior wall thickness and mass and cardiomyocyte cross-sectional area were similar between AngII-treated H-Ras knockout (H-ras(-/-) ) and control wild-type (H-ras(+/+) ) mice, as were extracellular matrix protein expression...
October 20, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29045529/impact-of-genetic-variations-in-the-mapk-signaling-pathway-on-outcome-in-metastatic-colorectal-cancer-patients-treated-with-first-line-folfiri-and-bevacizumab-data-from-fire-3-and-tribe-trials
#13
M D Berger, S Stintzing, V Heinemann, D Yang, S Cao, Y Sunakawa, Y Ning, S Matsusaka, S Okazaki, Y Miyamoto, M Suenaga, M Schirripa, S Soni, W Zhang, A Falcone, F Loupakis, H-J Lenz
Background: The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev)...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29026529/coordinating-erk-signaling-via-the-molecular-scaffold-kinase-suppressor-of-ras
#14
REVIEW
Danielle Frodyma, Beth Neilsen, Diane Costanzo-Garvey, Kurt Fisher, Robert Lewis
Many cancers, including those of the colon, lung, and pancreas, depend upon the signaling pathways induced by mutated and constitutively active Ras. The molecular scaffolds Kinase Suppressor of Ras 1 and 2 (KSR1 and KSR2) play potent roles in promoting Ras-mediated signaling through the Raf/MEK/ERK kinase cascade. Here we summarize the canonical role of KSR in cells, including its central role as a scaffold protein for the Raf/MEK/ERK kinase cascade, its regulation of various cellular pathways mediated through different binding partners, and the phenotypic consequences of KSR1 or KSR2 genetic inactivation...
2017: F1000Research
https://www.readbyqxmd.com/read/29019267/ge11-peptide-conjugated-selenium-nanoparticles-for-egfr-targeted-oridonin-delivery-to-achieve-enhanced-anticancer-efficacy-by-inhibiting-egfr-mediated-pi3k-akt-and-ras-raf-mek-erk-pathways
#15
Jiang Pi, Jinhuan Jiang, Huaihong Cai, Fen Yang, Hua Jin, Peihui Yang, Jiye Cai, Zheng W Chen
Selenium nanoparticles (Se NPs) have attracted increasing interest in recent decades because of their anticancer, immunoregulation, and drug carrier functions. In this study, GE11 peptide-conjugated Se NPs (GE11-Se NPs), a nanosystem targeting EGFR over-expressed cancer cells, were synthesized for oridonin delivery to achieve enhanced anticancer efficacy. Oridonin loaded and GE11 peptide conjugated Se NPs (GE11-Ori-Se NPs) were found to show enhanced cellular uptake in cancer cells, which resulted in enhanced cancer inhibition against cancer cells and reduced toxicity against normal cells...
November 2017: Drug Delivery
https://www.readbyqxmd.com/read/28993690/spred2-deficiecy-protects-mice-from-polymicrobial-septic-peritonitis-by-enhancing-inflammation-and-bacterial-clearance
#16
Junya Itakura, Miwa Sato, Toshihiro Ito, Megumi Mino, Soichiro Fushimi, Sakuma Takahashi, Teizo Yoshimura, Akihiro Matsukawa
Sepsis is an infection-induced systemic inflammatory syndrome and a major cause of death for critically ill patients. Here, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences host defense against polymicrobial sepsis (PMS) induced by cecal ligation and puncture (CLP). Compared to wild-type mice, Spred2(-/-) mice exhibited higher survival rates with increased level of leukocyte infiltration and local chemokine production and reduced plasma and peritoneal bacterial loads after CLP...
October 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28993193/%C3%AE-lipoic-acid-inhibits-human-lung-cancer-cell-proliferation-through-grb2-mediated-egfr-downregulation
#17
Lan Yang, Ya Wen, Guoqing Lv, Yuntao Lin, Junlong Tang, Jingxiao Lu, Manqiao Zhang, Wen Liu, Xiaojuan Sun
BACKGROUND: Alpha lipoic acid (α -LA) is a naturally occurring antioxidant and metabolic enzyme co-factor. Recently, α -LA has been reported to inhibit the growth of various cancer cells, but the precise signaling pathways that mediate the effects of α -LA on non-small cell lung cancer (NSCLC) development remain unclear. METHODS: The CCK-8 assay was used to assess cell proliferation in NSCLC cell lines after α -LA treatment. The expression of growth factor receptor-bound protein 2 (Grb2), cyclin-dependent kinase (CDK)-2, CDK4, CDK6, Cyclin D3, Cyclin E1, Ras, c-Raf, epidermal growth factor receptor (EGFR), ERK1/2 and activated EGFR and ERK1/2 was evaluated by western blotting...
December 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28982154/combined-mek-and-erk-inhibition-overcomes-therapy-mediated-pathway-reactivation-in-ras-mutant-tumors
#18
Mark Merchant, John Moffat, Gabriele Schaefer, Jocelyn Chan, Xi Wang, Christine Orr, Jason Cheng, Thomas Hunsaker, Lily Shao, Stephanie J Wang, Marie-Claire Wagle, Eva Lin, Peter M Haverty, Sheerin Shahidi-Latham, Hai Ngu, Margaret Solon, Jeffrey Eastham-Anderson, Hartmut Koeppen, Shih-Min A Huang, Jacob Schwarz, Marcia Belvin, Daniel Kirouac, Melissa R Junttila
Mitogen-activated protein kinase (MAPK) pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation...
2017: PloS One
https://www.readbyqxmd.com/read/28951457/mechanisms-of-acquired-resistance-to-braf-v600e-inhibition-in-colon-cancers-converge-on-raf-dimerization-and-are-sensitive-to-its-inhibition
#19
Rona Yaeger, Zhan Yao, David M Hyman, Jaclyn F Hechtman, Efsevia Vakiani, HuiYong Zhao, Wenjing Su, Lu Wang, Andrew Joelson, Andrea Cercek, José Baselga, Elisa de Stanchina, Leonard Saltz, Michael F Berger, David B Solit, Neal Rosen
BRAF V600E colorectal cancers (CRC) are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that CRC progression specimens invariably harbored lesions in elements of the RAS-RAF-MEK-ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in CRC patients that was not seen in similarly resistant melanomas...
September 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28950062/integrating-transcriptomic-data-with-mechanistic-systems-pharmacology-models-for-virtual-drug-combination-trials
#20
Anne Marie Barrette, Mehdi Bouhaddou, Marc R Birtwistle
Monotherapy clinical trials with mutation-targeted kinase inhibitors, despite some success in other cancers, have yet to impact glioblastoma (GBM). Besides insufficient blood-brain barrier penetration, combinations are key to overcoming obstacles such as intratumoral heterogeneity, adaptive resistance, and the epistatic nature of tumor genomics that cause mutation-targeted therapies to fail. With now hundreds of potential drugs, exploring the combination space clinically and preclinically is daunting. We are building a simulation-based approach that integrates patient-specific data with a mechanistic computational model of pan-cancer driver pathways (receptor tyrosine kinases, RAS/RAF/ERK, PI3K/AKT/mTOR, cell cycle, apoptosis, and DNA damage) to prioritize drug combinations by their simulated effects on tumor cell proliferation and death...
October 6, 2017: ACS Chemical Neuroscience
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