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RAS/RAF/ERK

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https://www.readbyqxmd.com/read/28534510/targeting-group-i-p21-activated-kinases-to-control-malignant-peripheral-nerve-sheath-tumor-growth-and-metastasis
#1
G Semenova, D S Stepanova, C Dubyk, E Handorf, S M Deyev, A J Lazar, J Chernoff
Malignant peripheral nerve sheath tumors (MPNSTs) are devastating sarcomas for which no effective medical therapies are available. Over 50% of MPSNTs are associated with mutations in NF1 tumor suppressor gene, resulting in activation of Ras and its effectors, including the Raf/Mek/Erk and PI3K/Akt/mTORC1 signaling cascades, and also the WNT/β-catenin pathway. As Group I p21-activated kinases (Group I Paks, PAK1/2/3) have been shown to modulate Ras-driven oncogenesis, we asked if these enzymes might regulate signaling in MPNSTs...
May 22, 2017: Oncogene
https://www.readbyqxmd.com/read/28513565/epidermal-growth-factor-receptor-cell-proliferation-signaling-pathways
#2
REVIEW
Ping Wee, Zhixiang Wang
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation...
May 17, 2017: Cancers
https://www.readbyqxmd.com/read/28504689/molecular-signaling-in-multiple-myeloma-association-of-ras-raf-mutations-and-mek-erk-pathway-activation
#3
J Xu, N Pfarr, V Endris, E K Mai, N H Md Hanafiah, N Lehners, R Penzel, W Weichert, A D Ho, P Schirmacher, H Goldschmidt, M Andrulis, M S Raab
Multiple myeloma (MM) is a plasma cell malignancy that is still considered to be incurable in most cases. A dominant mutation cluster has been identified in RAS/RAF genes, emphasizing the potential significance of RAS/RAF/MEK/ERK signaling as a therapeutic target. As yet, however, the clinical relevance of this finding is unclear as clinical responses to MEK inhibition in RAS-mutant MM have been mixed. We therefore assessed RAS/RAF mutation status and MEK/ERK pathway activation by both targeted sequencing and phospho-ERK immunohistochemistry in 180 tissue biopsies from 103 patients with newly diagnosed MM (NDMM) and 77 patients with relapsed/refractory MM (rrMM)...
May 15, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28497782/raf-proteins-exert-both-specific-and-compensatory-functions-during-tumour-progression-of-nras-driven-melanoma
#4
Coralie Dorard, Charlène Estrada, Céline Barbotin, Magalie Larcher, Alexandra Garancher, Jessy Leloup, Friedrich Beermann, Manuela Baccarini, Celio Pouponnot, Lionel Larue, Alain Eychène, Sabine Druillennec
NRAS and its effector BRAF are frequently mutated in melanoma. Paradoxically, CRAF but not BRAF was shown to be critical for various RAS-driven cancers, raising the question of the role of RAF proteins in NRAS-induced melanoma. Here, using conditional ablation of Raf genes in NRAS-induced mouse melanoma models, we investigate their contribution in tumour progression, from the onset of benign tumours to malignant tumour maintenance. We show that BRAF expression is required for ERK activation and nevi development, demonstrating a critical role in the early stages of NRAS-driven melanoma...
May 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28476040/efficacy-of-a-hsp90-inhibitor-ganetespib-in-preclinical-thyroid-cancer-models
#5
Shu-Fu Lin, Jen-Der Lin, Chuen Hsueh, Ting-Chao Chou, Chun-Nan Yeh, Ming-Huang Chen, Richard J Wong
Heat shock protein 90 is a molecular chaperon that maintains the correct folding and function of multiple client proteins. The inhibition of heat shock protein 90, which leads to the simultaneous degradation of multiple proteins involved in oncogenic signaling pathways, has revealed an innovative strategy to treat a variety of cancer types. We evaluated the therapeutic effects of ganetespib, a heat shock protein 90 inhibitor, in treating thyroid cancer. Ganetespib effectively inhibited cell proliferation in a dose-dependent manner in eight cell lines originating from four major histologic types of thyroid cancer (papillary, follicular, anaplastic and medullary)...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28473531/oncogenic-ras-regulates-long-non-coding-rna-orilnc1-in-human-cancer
#6
Dongmei Zhang, Gao Zhang, Xiaowen Hu, Lawrence Wu, Yi Feng, Sidan He, Youyou Zhang, Zhongyi Hu, Lu Yang, Tian Tian, Weiting Xu, Zhi Wei, Yiling Lu, Keith T Flaherty, Xiaomin Zhong, Gordon B Mills, Phyllis A Gimotty, Xiaowei Xu, Meenhard Herlyn, Lin Zhang
RAS and its downstream cascades transmit cellular signals resulting in increased transcription of genes involved in cell growth and division. Protein-coding gene targets of RAS signaling have been characterized extensively, but long non-coding RNAs (lncRNA) regulated by these processes have not. Using a custom-designed lncRNA microarray, we identified the lncRNA Orilnc1 as a genetic target of RAS that is critical for RAS oncogenicity. Orilnc1 expression was regulated by RAS-RAF-MEK-ERK signaling via the transcription factor AP1...
May 4, 2017: Cancer Research
https://www.readbyqxmd.com/read/28469964/comprehensive-pharmacological-profiling-of-neurofibromatosis-cell-lines
#7
Jianman Guo, Michael R Grovola, Hong Xie, Grace E Coggins, Patrick Duggan, Rukhsana Hasan, Jiale Huang, Danny W Lin, Claire Song, Gabriela M Witek, Simon Berritt, David C Schultz, Jeffrey Field
Patients with Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are predisposed to tumors of the nervous system. NF1 patients predominantly develop neurofibromas, and Malignant Peripheral Nerve Sheath Tumors (MPNST) while NF2 patients develop schwannomas and meningiomas. Here we quantified the drug sensitivities of NF1 and NF2 tumor cell lines in a high throughput platform. The platform contained a comprehensive collection of inhibitors of MEK, RAF, RAS, farnesyl transferase, PAK and ERK, representative drugs against many other cancer pathways including Wnt, Hedgehog, p53, EGF, HDAC, as well as classical cytotoxic agents recommended for treating MPNST, such as doxorubicin and etoposide...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28460481/shp2-is-induced-by-the-hbx-nf-%C3%AE%C2%BAb-pathway-and-contributes-to-fibrosis-during-human-early-hepatocellular-carcinoma-development
#8
Hyo Jeong Kang, Dal-Hee Chung, Chang Ohk Sung, Su Hyun Yoo, Eunsil Yu, Nayoung Kim, Sy-Hye Lee, Ji-Young Song, Chong Jai Kim, Jene Choi
The non-receptor tyrosine phosphatase SHP2 has scaffolding functions in signal transduction cascades downstream of growth receptors. A recent study suggested that SHP2 acts as a tumor suppressor during hepatocellular carcinoma (HCC) development. Herein we examined whether SHP2 links the HBx-NF-κB pathway to EGFR signaling during HCC development. The overexpression of HBx or NF-κB led to increased SHP2 expression via NF-κB binding to the Shp2 promoter. EGF treatment induced ERK activation as well as the rapid assembly of SHP2, EGFR, and Gab1...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28454211/targeting-the-ras-raf-mek-erk-pathway-in-hepatocellular-carcinoma
#9
Sufang Yang, Guohua Liu
Although the biological basis of hepatocellular carcinoma (HCC) remains unclear, effective treatments and improvement of the survival rate remain worthwhile research goals. Abnormal protein signaling pathways contributing to uncontrolled cell proliferation, differentiation, survival and apoptosis are biomarkers of the carcinogenic process. Certain mutated components or overexpression of the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway are increasingly being studied in HCC carcinogenesis...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28450315/mirna-mrna-network-involved-in-folliculogenesis-interactome-systems-biology-approach
#10
Abolfazl Bahrami, Seyed Reza Miraie-Ashtiani, Mostafa Sadeghi, Ali Najafi
At later phases of folliculogenesis, the mammalian ovarian follicle contains layers of granulosa cells surrounding an antral cavity. To better understand the molecular basis of follicular growth and granulosa cell maturation, we study transcriptome profiling of granulosa cells from small (< 5 mm) and large (> 10 mm) bovine follicles using simultaneous method of Affymetrix microarrays (24,128 probe sets) and RNA-Seq data sets. In this study proposes a computational method to discover the functional miRNA-mRNA regulatory modules, that is, groups of miRNAs and their target mRNAs that are believed to take part cooperatively in post-transcriptional gene regulation under specific conditions...
April 27, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28449575/visualisation-of-endogenous-erk1-2-in-cells-with-a-bioorthogonal-covalent-probe
#11
James Sipthorp, Honorine Lebraud, Rebecca Gilley, Andrew Kidger, Hanneke Okkenhaug, Marc K Saba-El-Leil, Sylvain Meloche, Christopher James Caunt, Simon Cook, Tom D Heightman
The RAS-RAF-MEK-ERK pathway has been intensively studied in oncology with RAS known to be mutated in ~30% of all human cancers. The recent emergence of ERK1/2 inhibitors and their ongoing clinical investigation demands a better understanding of ERK1/2 behaviour following small molecule inhibition. Although fluorescent fusion proteins and fluorescent antibodies are well-established methods to visualise proteins, we show that ERK1/2 can be visualised via a less invasive approach based on a two-step process using Inverse Electron Demand Diels-Alder cycloaddition...
April 28, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28445994/correction-amphiregulin-enhances-alpha6beta1-integrin-expression-and-cell-motility-in-human-chondrosarcoma-cells-through-ras-raf-mek-erk-ap-1-pathway
#12
Jui-Chieh Chen, Yu-Ju Chen, Chih-Yang Lin, Yi-Chin Fong, Chin-Jung Hsu, Chun-Hao Tsai, Jen-Liang Su, Chih-Hsin Tang
No abstract text is available yet for this article.
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424891/a-phase-i-dose-escalation-study-of-selumetinib-in-combination-with-erlotinib-or-temsirolimus-in-patients-with-advanced-solid-tumors
#13
Jeffrey R Infante, Roger B Cohen, Kevin B Kim, Howard A Burris, Gregory Curt, Ugochi Emeribe, Delyth Clemett, Helen K Tomkinson, Patricia M LoRusso
Background Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors...
April 19, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28423577/the-cyclin-like-protein-spy1-regulates-the-er%C3%AE-and-erk1-2-pathways-promoting-tamoxifen-resistance
#14
Rosa-Maria Ferraiuolo, Janice Tubman, Indrajit Sinha, Caroline Hamm, Lisa Ann Porter
The Ras/Raf/MEK/ERK pathway conveys growth factor and mitogen signalling to control the phosphorylation of a plethora of substrates regulating proliferation, survival, and migration. The Ras signalling pathway is frequently associated with poor prognosis and drug resistance in various cancers including those of the blood, breast and prostate. Activation of the downstream effector ERK does not always occur via a linear cascade of events; complicating the targeting of this pathway therapeutically. This work describes a novel positive feedback loop where the cell cycle regulatory factor Spy1 (RINGO; gene SPDYA) activates ERK1/2 in a MEK-independent fashion...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28407239/the-therapeutic-potential-of-targeting-the-braf-in-patients-with-colorectal-cancer
#15
REVIEW
Afsane Bahrami, AmirReza Hesari, Majid Khazaei, Seyed Mahdi Hassanian, Gordon Ferns, Amir Avan
Colorectal cancer is among the most lethal malignancies globally. BRAF is a member of the RAS/RAF/MEK/ERK signaling pathway. Its constitutive activation can result in increased cellular growth, development, invasion, and resistance to therapy. A mutation of the BRAF gene is present in 5-10% of metastatic colorectal cancers. BRAF mutations have been found to predict a lack of benefit to anti-EGFR therapy in metastatic CRC. Furthermore, CRC containing the BRAF V600E mutation display an innate resistance to BRAF inhibitors...
April 13, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28382169/integration-of-receptor-tyrosine-kinases-determines-sensitivity-to-pi3k%C3%AE-selective-inhibitors-in-breast-cancer
#16
Yi-Chao Xu, Xiang Wang, Yi Chen, Si-Meng Chen, Xin-Ying Yang, Yi-Ming Sun, Mei-Yu Geng, Jian Ding, Ling-Hua Meng
PI3Kα-selective inhibitor BYL719 is currently in phase II/III clinical trial for the treatment of breast cancer, but highly variable response has been observed among patients. We sought to discover predictive biomarker for the efficacy of BYL719 by dissecting the proliferative signaling pathway mediated by PI3K in breast cancer. BYL719 concurrently inhibited the phosphorylation of AKT and ERK in PIK3CA-mutated human breast cancer cells. PI3K-regulated ERK phosphorylation was independent of canonical PDK1/AKT/mTOR pathway, while it was associated with RAF/MEK...
2017: Theranostics
https://www.readbyqxmd.com/read/28376306/structure-guided-discovery-of-potent-and-selective-inhibitors-of-erk1-2-from-a-modestly-active-and-promiscuous-chemical-start-point
#17
Richard A Ward, Paul Bethel, Calum Cook, Emma Davies, Judit E Debreczeni, Gary Fairley, Lyman Feron, Vikki Flemington, Mark A Graham, Ryan Greenwood, Nicola Griffin, Lyndsey Hanson, Philip Hopcroft, Tina D Howard, Julian Hudson, Michael James, Clifford D Jones, Christopher R Jones, Scott Lamont, Richard Lewis, Nicola Lindsay, Karen Roberts, Iain Simpson, Steve St-Gallay, Steve Swallow, Jia Tang, Michael Tonge, Zhenhua Wang, Baochang Zhai
There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4...
April 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28370562/vitamin-c-at-high-concentrations-induces-cytotoxicity-in-malignant-melanoma-but-promotes-tumor-growth-at-low-concentrations
#18
Guang Yang, Yao Yan, Younan Ma, Yixin Yang
Vitamin C has been used in complementary and alternative medicine for cancers regardless of its ineffectiveness in clinical trials and the paradoxical effects antioxidants have on cancer. Vitamin C was found to induce cytotoxicity against cancers. However, the mechanisms of action have not been fully elucidated, and the effects of vitamin C on human malignant melanoma have not been examined. This study revealed that vitamin C at millimolar concentrations significantly reduced the cell viability as well as invasiveness, and induced apoptosis in human malignant melanoma cells...
March 30, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28367561/cancerous-perturbations-within-the-erk-pi3k-akt-and-wnt-%C3%AE-catenin-signaling-network-constitutively-activate-inter-pathway-positive-feedback-loops
#19
Rahul Rao Padala, Rishabh Karnawat, Satish Bharathwaj Viswanathan, Abhishek Vijay Thakkar, Asim Bikas Das
Perturbations in molecular signaling pathways are a result of genetic or epigenetic alterations, which may lead to malignant transformation of cells. Despite cellular robustness, specific genetic or epigenetic changes of any gene can trigger a cascade of failures, which result in the malfunctioning of cell signaling pathways and lead to cancer phenotypes. The extent of cellular robustness has a link with the architecture of the network such as feedback and feedforward loops. Perturbation in components within feedback loops causes a transition from a regulated to a persistently activated state and results in uncontrolled cell growth...
May 2, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28361341/cot-kinase-plays-a-critical-role-in-helicobacter-pylori-induced-il-8-expression
#20
Sungil Jang, Jinmoon Kim, Jeong-Heon Cha
Helicobacter pylori is a major pathogen causing various gastric diseases including gastric cancer. Infection of H. pylori induces pro-inflammatory cytokine IL-8 expression in gastric epithelial cells in the initial inflammatory process. It has been known that H. pylori can modulate Ras-Raf-Mek-Erk signal pathway for IL-8 induction. Recently, it has been shown that another signal molecule, cancer Osaka thyroid oncogene/tumor progression locus 2 (Cot/Tpl2) kinase, activates Mek and Erk and plays a role in the Erk pathway, similar to MAP3K signal molecule Raf kinase...
April 2017: Journal of Microbiology / the Microbiological Society of Korea
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