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https://www.readbyqxmd.com/read/28323034/co-targeting-of-egfr-and-autophagy-signaling-is-an-emerging-treatment-strategy-in-metastatic-colorectal-cancer
#1
Evangelos Koustas, Michalis V Karamouzis, Chrysovalantou Mihailidou, Dimitrios Schizas, Athanasios G Papavassiliou
The epidermal growth factor receptor (EGFR) and its associated pathway is a critical key regulator of CRC development and progression. The monoclonal antibodies (MoAbs) cetuximab and panitumumab, directed against EGFR, represent a major step forward in the treatment of metastatic Colorectal cancer (mCRC), in terms of progression-free survival and overall survival in several clinical trials. However, the activity of anti-EGFR moAbs appears to be limited to a subset of patients with mCRC. Studies have highlighted that acquired-resistance to anti-EGFR MoAbs biochemically converge into Ras/Raf/Mek/Erk and PI3K/Akt/mTOR pathways...
March 18, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28315521/systematic-morphological-profiling-of-human-gene-and-allele-function-via-cell-painting
#2
Mohammad Hossein Rohban, Shantanu Singh, Xiaoyun Wu, Julia B Berthet, Mark-Anthony Bray, Yashaswi Shrestha, Xaralabos Varelas, Jesse S Boehm, Anne E Carpenter
We hypothesized that human genes and disease-associated alleles might be systematically functionally annotated using morphological profiling of cDNA constructs, via a microscopy-based Cell Painting assay. Indeed, 50% of the 220 tested genes yielded detectable morphological profiles, which grouped into biologically meaningful gene clusters consistent with known functional annotation (e.g., the RAS-RAF-MEK-ERK cascade). We used novel subpopulation-based visualization methods to interpret the morphological changes for specific clusters...
March 18, 2017: ELife
https://www.readbyqxmd.com/read/28306189/map4k4-is-a-novel-mapk-erk-pathway-regulator-required-for-lung-adenocarcinoma-maintenance
#3
Xuan Gao, Guangming Chen, Chenxi Gao, Dennis Han Zhang, Shih-Fan Kuan, Laura P Stabile, Guoxiang Liu, Jing Hu
About 76% of lung adenocarcinoma patients harbor activating mutations in the receptor tyrosine kinase (RTK)/RAS/RAF pathways, leading to aberrant activation of the MAPK pathways particularly the MAPK/ERK pathway. However, many lung adenocarcinomas lacking these genomic mutations also display significant MAPK pathway activation, suggesting that additional MAPK pathway alterations remain undetected. This study has identified serine/threonine kinase mitogen-activated protein 4 kinase 4 (MAP4K4) as a novel positive regulator of MAPK/ERK signaling in lung adenocarcinoma...
March 17, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28302530/regorafenib-overcomes-chemotherapeutic-multidrug-resistance-mediated-by-abcb1-transporter-in-colorectal-cancer-in-vitro-and-in-vivo-study
#4
Yi-Jun Wang, Yun-Kai Zhang, Guan-Nan Zhang, Sweilem B Al Rihani, Meng-Ning Wei, Pranav Gupta, Xiao-Yu Zhang, Suneet Shukla, Suresh V Ambudkar, Amal Kaddoumi, Zhi Shi, Zhe-Sheng Chen
Chemotherapeutic multidrug resistance (MDR) is a significant challenge to overcome in clinic practice. Several mechanisms contribute to MDR, one of which is the augmented drug efflux induced by the upregulation of ABCB1 in cancer cells. Regorafenib, a multikinase inhibitor targeting the RAS/RAF/MEK/ERK pathway, was approved by the FDA to treat metastatic colorectal cancer and gastrointestinal stromal tumors. We investigated whether and how regorafenib overcame MDR mediated by ABCB1. The results showed that regorafenib reversed the ABCB1-mediated MDR and increased the accumulation of [(3)H]-paclitaxel in ABCB1-overexpressing cells by suppressing efflux activity of ABCB1, but not altering expression level and localization of ABCB1...
March 13, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28270557/raf1-braf-dimerization-integrates-the-signal-from-ras-to-erk-and-rok%C3%AE
#5
Andrea Varga, Karin Ehrenreiter, Bertram Aschenbrenner, Pawel Kocieniewski, Marek Kochanczyk, Tomasz Lipniacki, Manuela Baccarini
Downstream of growth factor receptors and of the guanine triphosphatase (GTPase) RAS, heterodimers of the serine/threonine kinases BRAF and RAF1 are critical upstream kinases and activators of the mitogen-activated protein kinase (MAPK) module containing the mitogen-activated and extracellular signal-regulated kinase kinase (MEK) and their targets, the extracellular signal-regulated kinase (ERK) family. Either direct or scaffold protein-mediated interactions among the components of the ERK module (the MAPKKKs BRAF and RAF1, MEK, and ERK) facilitate signal transmission...
March 7, 2017: Science Signaling
https://www.readbyqxmd.com/read/28264648/a-phase-i-dose-escalation-study-of-selumetinib-in-combination-with-docetaxel-or-dacarbazine-in-patients-with-advanced-solid-tumors
#6
Patricia M LoRusso, Jeffrey R Infante, Kevin B Kim, Howard A Burris, Gregory Curt, Ugochi Emeribe, Delyth Clemett, Helen K Tomkinson, Roger B Cohen
BACKGROUND: The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors...
March 6, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28262927/targeting-the-ras-signaling-pathway-as-a-potential-therapeutic-target-in-the-treatment-of-colorectal-cancer
#7
REVIEW
Afsane Bahrami, Seyed Mahdi Hassanian, Soodabeh ShahidSales, Zahra Farjami, Malihe Hasanzadeh, Kazem Anvari, Amir Aledavood, Mina Maftouh, Gordon A Ferns, Majid Khazaei, Amir Avan
The V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is an important pathways that is frequently dysregulated in colorectal cancer (CRC). It is involved in the modulation of several downstream effectors, that include: Raf/Mek/Erk, PI3K/Akt, RalGDS/p38MAPK and Rac/Rho, and thereby influences tumorigenesis, the invasive behaviors of tumor cell, and resistance to therapy. There is growing evidence exploring the use of drugs that target these pathways in the treatment of CRC. Cetuximab has been approved for CRC patients without a KRAS mutation, or for EGFR-expressing metastatic CRC, although most of the patients have a mutation of KRAS and NRAS...
March 6, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28243112/induction-of-pd-l1-expression-by-epidermal-growth-factor-receptor-mediated-signaling-in-esophageal-squamous-cell-carcinoma
#8
Wencheng Zhang, Qingsong Pang, Cihui Yan, Qifeng Wang, Jingsong Yang, Shufei Yu, Xiao Liu, Zhiyong Yuan, Ping Wang, Zefen Xiao
PURPOSE: The purpose of this study was to investigate the potential effect of activation of epidermal growth factor receptor (EGFR) signaling pathway on the expression of programmed death-ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) cells with EGFR overexpression. METHODS: Flow cytometry and Western blot methods were used to assess PD-L1 expression on ESCC cells when EGFR signaling pathway was activated by epidermal growth factor (EGF) with or without EGFR-specific inhibitor AG-1478, and then EGFR signaling array was applied to analyze the potential signaling pathways involved...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28188228/time-resolved-phosphoproteome-analysis-of-paradoxical-raf-activation-reveals-novel-targets-of-erk
#9
Peter Kubiniok, Hugo Lavoie, Marc Therrien, Pierre Thibault
Small molecules targeting aberrant RAF activity, like Vemurafenib (PLX4032), are highly effective against cancers harboring the V600E BRAF mutation, and are now approved for clinical use against metastatic melanoma. However, in tissues showing elevated RAS activity and in RAS-mutant tumors, these inhibitors stimulate RAF dimerization, resulting in inhibitor resistance and downstream paradoxical ERK activation. To understand the global signaling response of cancer cells to RAF inhibitors, we profiled the temporal changes of the phosphoproteome of two colon cancer cell lines (Colo205 and HCT116) that respond differently to Vemurafenib...
February 10, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28180061/kinase-suppressor-of-ras-2-ksr2-expression-in-the-brain-regulates-energy-balance-and-glucose-homeostasis
#10
Lili Guo, Diane L Costanzo-Garvey, Deandra R Smith, Beth K Neilsen, Richard G MacDonald, Robert E Lewis
OBJECTIVE: Kinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that is expressed at high levels in the brain. KSR2 disruption in humans and mice causes obesity and insulin resistance. Understanding the anatomical location and mechanism of KSR2 function should lead to a better understanding of physiological regulation over energy balance. METHODS: Mice bearing floxed alleles of KSR2 (KSR2(fl/fl)) were crossed with mice expressing the Cre recombinase expressed by the Nestin promoter (Nes-Cre) to produce Nes-CreKSR2(fl/fl) mice...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28174173/the-apc-c-e3-ligase-complex-activator-fzr1-restricts-braf-oncogenic-function
#11
Lixin Wan, Ming Chen, Juxiang Cao, Xiangpeng Dai, Qing Yin, Jinfang Zhang, Su-Jung Song, Ying Lu, Jing Liu, Hiroyuki Inuzuka, Jesse M Katon, Kelsey Berry, Jacqueline Fung, Christopher Ng, Pengda Liu, Min Sup Song, Lian Xue, Roderick T Bronson, Marc W Kirschner, Rutao Cui, Pier Paolo Pandolfi, Wenyi Wei
BRAF drives tumorigenesis by coordinating the activation of the RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathways governing BRAF kinase activity and protein stability remain undefined. Here, we report that in primary cells with active APC(FZR1), APC(FZR1) earmarks BRAF for ubiquitination-mediated proteolysis, whereas in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization. Moreover, we identified FZR1 as a direct target of ERK and CYCLIN D1/CDK4 kinases...
February 7, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28161506/mathematical-modelling-unveils-the-essential-role-of-cellular-phosphatases-in-the-inhibition-of-raf-mek-erk-signalling-by-sorafenib-in-hepatocellular-carcinoma-cells
#12
Zuzana Saidak, Anne-Sophie Giacobbi, Christophe Louandre, Chloé Sauzay, Youcef Mammeri, Antoine Galmiche
The RAS-RAF-MEK-ERK cascade is a key oncogenic signal transduction pathway activated in many types of tumours in humans. Sorafenib, the medical treatment of reference against advanced stages of hepatocellular carcinoma (HCC), inhibits the RAF-MEK-ERK cascade in HCC cells. Based on previous studies suggesting that this cascade is an important target of sorafenib in HCC cells, we explored its regulation using mathematical modelling and ordinary differential equations. We analysed the dynamic regulation of the core components of the RAF-MEK-ERK cascade in three human HCC cell lines (Huh7, Hep3B and PLC/PRF5) with heterogeneous responses to sorafenib...
February 2, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28131904/potential-therapeutic-targets-of-epithelial-mesenchymal-transition-in-melanoma
#13
Ross L Pearlman, Mary Katherine Montes de Oca, Harish Chandra Pal, Farrukh Afaq
Melanoma is a cutaneous neoplastic growth of melanocytes with great potential to invade and metastasize, especially when not treated early and effectively. Epithelial-mesenchymal transition (EMT) is the process by which melanocytes lose their epithelial characteristics and acquire mesenchymal phenotypes. Mesenchymal protein expression increases the motility, invasiveness, and metastatic potential of melanoma. Many pathways play a role in promotion of mesenchymal protein expression including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, and several others...
January 25, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28100485/quantification-of-growth-factor-signaling-and-pathway-crosstalk-by-live-cell-imaging
#14
Sean M Gross, Peter Rotwein
Peptide growth factors stimulate cellular responses through activation of their trans-membrane receptors. Multiple intracellular signaling cascades are engaged following growth factor - receptor binding, leading to short- and long-term biological effects. Each receptor-activated signaling pathway does not act in isolation, but rather interacts at different levels with other pathways to shape signaling networks that are distinctive for each growth factor. To gain insights into the specifics of growth factor-regulated interactions among different signaling cascades, we developed a HeLa cell line stably expressing fluorescent live-cell imaging reporters that are readouts for two major growth factor-stimulated pathways, Ras - Raf - Mek - Erk and PI3-kinase - Akt...
January 18, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28093501/discrete-cytosolic-macromolecular-braf-complexes-exhibit-distinct-activities-and-composition
#15
Britta Diedrich, Kristoffer Tg Rigbolt, Michael Röring, Ricarda Herr, Stephanie Kaeser-Pebernard, Christine Gretzmeier, Robert F Murphy, Tilman Brummer, Jörn Dengjel
As a central element within the RAS/ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. Consequently, it has emerged as an important therapeutic target in various malignancies. Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. By applying SEC-PCP-SILAC, we analyzed protein-protein interactions of hyperactive BRAF(V)(600E) and wild-type BRAF (BRAF(WT))...
March 1, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28069929/genomic-alterations-of-adamantinomatous-and-papillary-craniopharyngioma
#16
Tobias Goschzik, Marco Gessi, Verena Dreschmann, Ursel Gebhardt, Linghua Wang, Shigeru Yamaguchi, David A Wheeler, Libero Lauriola, Ching C Lau, Hermann L Müller, Torsten Pietsch
Craniopharyngiomas are rare histologically benign but clinically challenging neoplasms. To obtain further information on the molecular genetics and biology of craniopharyngiomas, we analyzed a cohort of 121 adamantinomatous and 16 papillary craniopharyngiomas (ACP, PCP). We extracted DNA from formalin-fixed paraffin-embedded tissue and determined mutational status of CTNNB1, BRAF, and DDX3X by Sanger sequencing, next generation panel sequencing, and pyrosequencing. Sixteen craniopharyngiomas were further analyzed by molecular inversion profiling (MIP); 76...
January 9, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28068326/klf4-is-regulated-by-ras-raf-mek-erk-signaling-through-e2f1-and-promotes-melanoma-cell-growth
#17
M Riverso, V Montagnani, B Stecca
Melanoma is the most lethal form of skin cancer and treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors show only temporary benefit due the occurrence of resistance and immunotherapy is effective only in a subset of patients. To improve patient survival, there is a need to better understand molecular mechanisms that drive melanoma growth and operate downstream of the mitogen activated protein kinase (MAPK) signaling. The Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays a critical role in embryonic development, stemness and cancer, where it can act either as oncogene or tumor suppressor...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28067893/vemurafenib-and-trametinib-reduce-expression-of-ctgf-and-il-8-in-v600e-braf-melanoma-cells
#18
Mariusz L Hartman, Michal Rozanski, Marta Osrodek, Izabela Zalesna, Malgorzata Czyz
Clinical evidence has revealed that while RAS/RAF/MEK/ERK pathway is a crucial component of melanomagenesis, other signaling pathways can also contribute to the malignant growth and development of resistance to targeted therapies. We explored the response of (V600E)BRAF melanoma cells derived from surgical specimens and grown in stem cell medium to vemurafenib and trametinib, drugs targeting the activity of (V600E)BRAF and MEK1/2, respectively. Cell growth and apoptosis were monitored by real-time imaging system, immunophenotype and cell cycle by flow cytometry, gene expression by quantitative real-time PCR, immunoblotting and enzyme-linked immunosorbent assay...
January 9, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28059052/gastrin-enhances-autophagy-and-promotes-gastric-carcinoma-proliferation-via-inducing-ampk%C3%AE
#19
Zhuang Kun, Guo Hanqing, Tang Hailing, Yan Yuan, Zhang Jun, Zhang Lingxia, Han Kun, Zhang Xin
Gastric cancer (GC) is one of the most frequent epithelial malignancies worldwide. The gastrointestinal (GI) peptide gastrin is an important regulator of the secretion and release of gastric acid from stomach parietal cells and it also plays a vital role in the development and progression of gastric cancer. The aim of the current study was to investigate the role and underlying mechanism of gastrin and autophagy in regulating gastric cancer tumorigenesis. Gastrin-17 amide (G-17) was applied in the gastric cancer cell lines SGC7901 and MGC-803...
January 5, 2017: Oncology Research
https://www.readbyqxmd.com/read/28051352/antisense-oligonucleotides-targeting-raf-1-block-japanese-encephalitis-virus-in-vitro-and-in-vivo
#20
Li Zhang, Qingjun Li, Xiaoran Ding, Bo Zhang, Qiling Zhang, Xinyan Qu, Yujia Huo, Jing Yang, Shengqi Wang
Japanese encephalitis virus (JEV) infections represent a major health concern in Southeast Asia since no effective treatments are available. Recently, several reports have demonstrated that inhibition of certain host cell proteins prevents viral infection. Raf-1 kinase is a central component of many signaling pathways involved in normal cell growth and oncogenic transformation, and Ras/Raf/ERK signaling activation has been observed during viral infections (including JEV infection). In this study, Raf-1 was confirmed to be upregulated by JEV infection, which suggested that Raf-1 might be important for JEV infection and might be a target for novel anti-JEV drugs...
January 4, 2017: Nucleic Acid Therapeutics
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