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RAS/RAF/ERK

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https://www.readbyqxmd.com/read/29778238/interplay-between-estrogen-related-receptors-and-steroidogenesis-controlling-molecules-in-adrenals-in-vivo-and-in-vitro-study
#1
A Pacwa, E Gorowska-Wojtowicz, A Ptak, P Pawlicki, A Milon, M Sekula, K Lesniak, B Bilinska, A Hejmej, M Kotula-Balak
Estrogen-related receptors (ERRs) α, β and γ appear to be novel molecules implicated in estrogen signaling. We blocked and activated ERRs in mouse (C57BL/6) adrenals and adrenocortical cells (H295R) using pharmacological agents XCT 790 (ERRα antagonist) and DY131 (ERRβ/γ agonist), respectively. Mice were injected with XCT 790 or DY131 (5 μg/kg bw) while cells were exposed to XCT 790 or DY131 (0.5 μg/L). Irrespectively of the agent used, changes in adrenocortical cell morphology along with changes in lutropin, cholesterol levels and estrogen production were found...
May 16, 2018: Acta Histochemica
https://www.readbyqxmd.com/read/29777330/down-regulating-il-6-gp130-targets-improved-the-anti-tumor-effects-of-5-fluorouracil-in-colon-cancer
#2
Sanhong Li, Jilai Tian, Hongming Zhang, Shoubing Zhou, Xiyong Wang, Lei Zhang, Jiapeng Yang, Zhigang Zhang, Zhenling Ji
Recent studies have confirmed that IL-6/GP130 targets are closely associated with tumor growth, metastasis and drug resistance. 5-Fluorouracil (5-FU) is the most common chemotherapeutic agent for colon cancer but is limited due to chemoresistance and high cytotoxicity. Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator, was discovered by multiple ligand simultaneous docking and drug repositioning approaches to have a novel function as an IL-6/GP130 target inhibitor. Thus, we speculated that in colon cancer, the anti-tumor efficacy of 5-FU might be increased in combination with IL-6/GP130 inhibitors...
May 18, 2018: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/29768711/clinical-resistance-associated-with-a-novel-map2k1-mutation-in-a-patient-with-langerhans-cell-histiocytosis
#3
David O Azorsa, David W Lee, Daniel H Wai, Ranjan Bista, Apurvi R Patel, Eiman Aleem, Michael M Henry, Robert J Arceci
Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p...
May 16, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29760222/erk-mutations-and-amplification-confer-resistance-to-erk-inhibitor-therapy
#4
Bijay S Jaiswal, Steffen Durinck, Eric Stawiski, Jianping Yin, Weiru Wang, Eva Lin, John G Moffat, Scott Martin, Zora Modrusan, Somasekar Seshagiri
PURPOSE: MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF and/or RAS mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance...
May 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29757973/a-new-strategy-to-control-and-eradicate-undruggable-oncogenic-k-ras-driven-pancreatic-cancer-molecular-insights-and-core-principles-learned-from-developmental-and-evolutionary-biology
#5
REVIEW
Robert E Van Sciver, Michael P Lee, Caroline Dasom Lee, Alex C Lafever, Elizaveta Svyatova, Kevin Kanda, Amber L Colliver, Lauren L Siewertsz van Reesema, Angela M Tang-Tan, Vasilena Zheleva, Monicah N Bwayi, Minglei Bian, Rebecca L Schmidt, Lynn M Matrisian, Gloria M Petersen, Amy H Tang
Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely "undruggable". Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH)...
May 14, 2018: Cancers
https://www.readbyqxmd.com/read/29749533/egf-upregulates-rfpl3-and-htert-via-the-mek-signaling-pathway-in-non%C3%A2-small-cell-lung-cancer-cells
#6
Chuan Lin, Yu Qin, Hua Zhang, Ming-Yang Gao, Yan-Fu Wang
Activation of the epidermal growth factor receptor (EGFR) during tumor development can trigger the MEK signaling pathway. In the present study, we investigated the MEK signaling pathway in non‑small cell lung cancer (NSCLC) cells with respect to the effect of epidermal growth factor (EGF) on expression of Ret finger protein like 3 (RFPL3) and human telomerase reverse transcriptase (hTERT), and the effect of RFPL3 overexpression on other MEK signaling proteins. In vitro, A549 and H1299 cells were treated with different concentrations of EGF for 24 h or 48 h...
May 8, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29732117/isoform-selective-activity-based-profiling-of-erk-signaling
#7
Myungsun Shin, Caroline E Franks, Ku-Lung Hsu
Extracellular signal-regulated kinases (ERKs) mediate downstream signaling of RAS-RAF-MEK as key regulators of the mitogen-activated protein kinase (MAPK) pathway. Activation of ERK signaling is a hallmark of cancer and upstream MAPK proteins have been extensively pursued as drug targets for cancer therapies. However, the rapid rise of resistance to clinical RAF and MEK inhibitors has prompted interest in targeting ERK (ERK1 and ERK2 isoforms) directly for cancer therapy. Current methods for evaluating activity of inhibitors against ERK isoforms are based primarily on analysis of recombinant proteins...
March 7, 2018: Chemical Science
https://www.readbyqxmd.com/read/29721377/oncolytic-influenza-virus-infection-restores-immunocompetence-of-lung-tumor-associated-alveolar-macrophages
#8
Dörthe Masemann, Katharina Köther, Meike Kuhlencord, Georg Varga, Johannes Roth, Brian Dennis Lichty, Ulf Rüdiger Rapp, Viktor Wixler, Stephan Ludwig
Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer and demonstrates high resistance to radiation and chemotherapy. These tumors evade immune system detection by promoting an immunosuppressive tumor microenvironment. Genetic analysis has revealed oncogenic activation of the Ras/Raf/MEK/ERK signaling pathway to be a hallmark of NSCLCs, which promotes influenza A virus (IAV) infection and replication in these cells. Thus, we aimed to unravel the oncolytic properties of IAV infection against NSCLCs in an immunocompetent model in vivo ...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29708446/braf-mutant-colorectal-cancer-a-different-breed-evolving
#9
E Lai, A Pretta, V Impera, S Mariani, R Giampieri, L Casula, V Pusceddu, P Coni, D Fanni, M Puzzoni, L Demurtas, P Ziranu, G Faa, M Scartozzi
BRAF mutant colorectal cancer (BRAF MT CRC) is a unique category of colorectal tumour with peculiar molecular, pathological and clinical features and poor prognosis; despite recent research, BRAF mutation predictive value and standard treatment of BRAF MT CRC still have to be defined. In this review, we focused on this challenging topic. Areas Covered: The potential use of BRAF mutational status among recent additional prognostic and predictive indicators and current treatment strategy in use in these patients is discussed...
April 30, 2018: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/29691253/the-inhibitory-nkr-p1b-clr-b-recognition-axis-facilitates-detection-of-oncogenic-transformation-and-cancer-immunosurveillance
#10
Miho Tanaka, Jason H Fine, Christina L Kirkham, Oscar A Aguilar, Antoaneta Belcheva, Alberto Martin, Troy Ketela, Jason Moffat, David Sj Allan, James R Carlyle
Natural killer (NK) cells express receptors specific for MHC class I (MHC-I) molecules involved in "missing-self" recognition of cancer and virus-infected cells. Here we elucidate the role of MHC-I-independent NKR-P1B:Clr-b interactions in the detection of oncogenic transformation by NK cells. Ras oncogene overexpression was found to promote a real-time loss of Clr-b on mouse fibroblasts and leukemia cells, mediated in part via the Raf/MEK/ERK and PI3K pathways. Ras-driven Clr-b downregulation occurred at the level of the Clrb (Clec2d) promoter, nascent Clr-b transcripts, and cell surface Clr-b protein, in turn promoting missing-self recognition via the NKR-P1B inhibitory receptor...
April 24, 2018: Cancer Research
https://www.readbyqxmd.com/read/29683208/a-novel-tricarbonylmethane-agent-cmc2-24-reduces-human-pancreatic-tumor-growth-in-mice-by-targeting-ras
#11
Naveen A Mallangada, Joselin M Vargas, Swaroopa Thomas, Matthew G DiGiovanni, Brandon M Vaeth, Matthew D Nemesure, Ruixue Wang, Joseph F LaComb, Jennie L Williams, Lorne M Golub, Francis Johnson, Gerardo G Mackenzie
Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (p < 0...
April 23, 2018: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29662665/molecular-mechanism-of-action-and-potential-biomarkers-of-growth-inhibition-of-synergistic-combination-of-afatinib-and-dasatinib-against-gefitinib-resistant-non-small-cell-lung-cancer-cells
#12
Miao Wang, Alex Yuang-Chi Chang
Epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) is the first choice of treatment for advanced non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, single agent usually has limited efficacy due to heterogeneous resistant mechanisms of cancer cells. Thus drug combination therapy would offer more benefits by synergistic interactions and avoidance of resistance emergence. In this study, we selected 8 NSCLC cell lines with different genetic characteristics as research models to investigate the efficacy of 4 agents (gefitinib, cetuximab, afatinib and dasatinib) and their combinations...
March 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29660312/the-egf-ras-pathway-controls-growth-in-drosophila-via-ribosomal-rna-synthesis
#13
Shrivani Sriskanthadevan-Pirahas, Joshua Lee, Savraj S Grewal
The Ras small G-protein is a conserved regulator of cell and tissue growth during animal development. Studies in Drosophila have shown how Ras can stimulate a Raf-MEK-ERK signaling pathway to control cell growth and proliferation in response to epidermal growth factor (EGF) stimulation. This work has also defined several transcription factors that can function as downstream growth effectors of EGF/Ras/ERK pathway by stimulating mRNA transcription. Here we report on stimulation of RNA polymerase I (Pol I)-mediated ribosomal RNA (rRNA) synthesis as a growth effector of Ras/ERK signalling in Drosophila...
April 13, 2018: Developmental Biology
https://www.readbyqxmd.com/read/29615470/modulation-of-gq-rho-signaling-by-the-erk-mapk-pathway-controls-locomotion-in-caenorhabditis-elegans
#14
Brantley Coleman, Irini Topalidou, Michael Ailion
The heterotrimeric G protein Gq regulates neuronal activity through distinct downstream effector pathways. In addition to the canonical Gq effector phospholipase Cb, the small GTPase Rho was recently identified as a conserved effector of Gq. To identify additional molecules important for Gq signaling in neurons, we performed a forward genetic screen in the nematode Caenorhabditis elegans for suppressors of the hyperactivity and exaggerated waveform of an activated Gq mutant. We isolated two mutations affecting the MAP kinase scaffold protein KSR-1 and found that KSR-1 modulates locomotion downstream of or in parallel to the Gq-Rho pathway...
April 3, 2018: Genetics
https://www.readbyqxmd.com/read/29574749/targeting-egfr-mediated-autophagy-as-a-potential-strategy-for-cancer-therapy
#15
REVIEW
Mopa Alina Sooro, Ni Zhang, Pinghu Zhang
Autophagy is a naturally-occurring programmed cellular catabolic process stimulated by cellular stress for energy homeostasis maintenance and elimination of harmful substances. It mostly works as pro-survival mechanism but on the other hand deregulation of autophagy has been linked to non-apoptotic cell death known as 'type II programmed cell death'. Emerging evidences indicate that EGFR (epidermal growth factor receptor)-mediated RAS-RAF-MEK-ERK signaling pathway plays a critical role in the induction of autophagy in various tumors...
March 25, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29573266/sorafenib-paradoxically-activates-the-ras-raf-erk-pathway-in-polyclonal-human-nk-cells-during-expansion-and-thereby-enhances-effector-functions-in-a-dose-and-time-dependent-manner
#16
Julian Lohmeyer, Thomas Nerreter, Julia Dotterweich, Hermann Einsele, Ruth Seggewiss-Bernhardt
Natural killer (NK) cells play a major role in host immunity against leukemia and lymphoma. However, clinical trials applying NK cells have not been as efficient as hoped for. Patients treated with RAF inhibitors exhibit increased tumor infiltration by immune cells suggesting that a combination of RAF inhibitors with immunotherapy might be beneficial. As MAPKs such as CRAF regulate NK cell functions, we performed an in vitro investigation on the potential of clinically relevant short acting tyrosine kinase inhibitors (TKIs) as potential adjuvants for NK cell therapy: NK cells from healthy human blood donors were thus treated with sorafenib, sunitinib or the pan-RAF inhibitor ZM336372 during ex vivo expansion...
March 24, 2018: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/29563190/tropomyosin-receptor-kinase-a-novel-target-in-screened-neuroendocrine-tumors
#17
Elke Tatjana Aristizabal Prada, Vera Heinzle, Thomas Knösel, Svenja Nölting, Gerald Spoettl, Julian Maurer, Christine Spitzweg, Martin Angele, Nina Schmidt, Felix Beuschlein, Günter K Stalla, Rainer Blaser, Klaus A Kuhn, Christoph J Auernhammer
Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability...
March 21, 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29545922/mek-inhibition-leads-to-brca2-downregulation-and-sensitization-to-dna-damaging-agents-in-pancreas-and-ovarian-cancer-models
#18
Francesca Vena, Ruochen Jia, Arman Esfandiari, Juan J Garcia-Gomez, Manuel Rodriguez-Justo, Jianguo Ma, Sakeena Syed, Lindsey Crowley, Brian Elenbaas, Samantha Goodstal, John A Hartley, Daniel Hochhauser
Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines...
February 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29540830/classifying-braf-alterations-in-cancer-new-rational-therapeutic-strategies-for-actionable-mutations
#19
REVIEW
Matthew Dankner, April A N Rose, Shivshankari Rajkumar, Peter M Siegel, Ian R Watson
The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants...
March 15, 2018: Oncogene
https://www.readbyqxmd.com/read/29536301/expression-profiles-of-genes-potential-therapy-targets-and-their-relationship-to-survival-in-renal-cell-carcinoma
#20
N V Apanovich, M V Peters, P V Apanovich, B Sh Kamolov, V B Matveev, E K Ginter, A V Karpukhin
The main mechanisms of pathogenesis of clear cell renal cell carcinoma (CCRCC) are realized through the PI3K-AKT-mTOR and Ras-RAF-ERK signaling pathways. Targeted therapy is directed primarily at the genes and their encoded products that are components of these pathways. The levels of expression and coexpression of target genes were determined, and the difference in the functioning of the genes of one of the two major signaling pathways in tumors of CCRCC patients with different life duration (more and less than 3...
January 2018: Doklady. Biochemistry and Biophysics
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