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https://www.readbyqxmd.com/read/29440765/baicalin-induces-cellular-senescence-in-human-colon-cancer-cells-via-upregulation-of-depp-and-the-activation-of-ras-raf-mek-erk-signaling
#1
Zhou Wang, Lingman Ma, Mengqi Su, Yiran Zhou, Ke Mao, Chengqin Li, Guangyong Peng, Changlin Zhou, Baiyong Shen, Jie Dou
Baicalin is a natural flavonoid glycoside which has potent anti-tumor and antioxidant activity in cancer cells. In the present study, we found that baicalin treatment significantly induced senescence in colon cancer cells. Furthermore, baicalin upregulated the expression of decidual protein induced by progesterone (DEPP) in HCT116 colon cancer cells, which accompanied with the activation of Ras/Raf/MEK/ERK and p16 INK4A /Rb signaling pathways. Meanwhile, these phenomena also appeared under the anti-oxidation effect exerted by baicalin...
February 13, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29440321/targeting-the-mapk-pathway-in-ras-mutant-cancers
#2
Sarah G Hymowitz, Shiva Malek
Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this review, we highlight the challenges and opportunities in targeting KRAS mutant tumors through inhibition of mitogen-activated protein kinase (MAPK) signaling with conformation-specific kinase inhibitors. Through structural analysis and mechanistic studies with BRAF and mitogen-activated protein kinase (MEK) inhibitors, we describe how kinase-dependent and -independent functions of MAPK signaling components regulate KRAS-driven tumorigenesis and how these insights can be used to treat RAS mutant cancers with small molecule kinase inhibitors...
February 12, 2018: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29437873/brain-distribution-of-a-novel-mek-inhibitor-e6201-implications-in-the-treatment-of-melanoma-brain-metastases
#3
Gautham Gampa, Minjee Kim, Nicholas Cook-Rostie, Janice Laramy, Jann N Sarkaria, Linda Paradiso, Louis DePalatis, William F Elmquist
Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and MEK has been identified to be an important target. E6201 is a potent synthetic small molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the BBB on the CNS exposure of E6201...
February 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29437705/nras-mutated-rhabdomyosarcoma-cells-are-vulnerable-to-mitochondrial-apoptosis-induced-by-co-inhibition-of-mek-and-pi3k%C3%AE
#4
Simone Fulda, Nadezda Dolgikh, Manuela Hugle, Meike Vogler
Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here we report that co-inhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wildtype, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wildtype RMS tumors in vivo...
February 6, 2018: Cancer Research
https://www.readbyqxmd.com/read/29436617/ripk4-pebp1-axis-promotes-pancreatic-cancer-cell-migration-and-invasion-by-activating-raf1-mek-erk-signaling
#5
Zi-Hao Qi, Hua-Xiang Xu, Shi-Rong Zhang, Jin-Zhi Xu, Shuo Li, He-Li Gao, Wei Jin, Wen-Quan Wang, Chun-Tao Wu, Quan-Xing Ni, Xian-Jun Yu, Liang Liu
Pancreatic cancer is a lethal disease with a high metastatic potential. In our previous study, we identified a specific subgroup of patients with pancreatic cancer with a serum signature of carcinoembryonic antigen (CEA)+/cancer antigen (CA)125+/CA19-9 ≥1,000 U/ml. In this study, by using high-throughput screening analysis, we found that receptor-interacting protein kinases 4 (RIPK4) may be a key molecule involved in the high metastatic potential of this subgroup of patients with pancreatic cancer. A high RIPK4 expression predicted a poor prognosis and promoted pancreatic cancer cell migration and invasion via the RAF1/MEK/ERK pathway...
February 7, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29435178/inhibition-of-the-mek-erk-pathway-augments-nab-paclitaxel-based-chemotherapy-effects-in-preclinical-models-of-pancreatic-cancer
#6
Niranjan Awasthi, Sheena Monahan, Alexis Stefaniak, Margaret A Schwarz, Roderich E Schwarz
Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29435137/activation-of-mapk-signalling-results-in-resistance-to-saracatinib-azd0530-in-ovarian-cancer
#7
Niamh McGivern, Aya El-Helali, Paul Mullan, Iain A McNeish, D Paul Harkin, Richard D Kennedy, Nuala McCabe
SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29435119/a-dual-mechanism-of-activation-of-the-sonic-hedgehog-pathway-in-anaplastic-thyroid-cancer-crosstalk-with-ras-braf-mek-pathway-and-ligand-secretion-by-tumor-stroma
#8
Alessia Parascandolo, Mikko O Laukkanen, Nancy De Rosa, Clara Ugolini, Maria Carmela Cantisani, Anna Maria Cirafici, Fulvio Basolo, Massimo Santoro, Maria Domenica Castellone
Sonic Hedgehog (Shh) pathway regulates embryonic development of different organs including the thyroid gland. The aberrant activation of Shh signaling has been found in several types of cancer and according to recent evidences it represents an important regulator of tumor-stroma interaction. In this study, we have analyzed expression, activation and molecular mechanisms regulating the Shh pathway and its involvement in the modulation of tumor stroma interaction in anaplastic thyroid cancer (ATC) cells. Our results suggest that Shh signaling undergoes a dual mechanism of induction in ATC cells: 1) a basal non-canonical Smo-dependent activation of Gli transcription factor that is partly caused by interaction with the RAS/BRAF/MEK oncogenic pathway and is characterized by the absence of Shh ligand expression in thyroid cancer cells and 2) a paracrine response of cancer cells to Shh ligand secreted by tumor stroma (fibroblasts and mesenchymal stromal cells, MSCs) inducing cancer cell migration and in vitro tumorigenesis...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29433126/mek-drives-braf-activation-through-allosteric-control-of-ksr-proteins
#9
Hugo Lavoie, Malha Sahmi, Pierre Maisonneuve, Sara A Marullo, Neroshan Thevakumaran, Ting Jin, Igor Kurinov, Frank Sicheri, Marc Therrien
RAF family kinases have prominent roles in cancer. Their activation is dependent on dimerization of their kinase domains, which has emerged as a hindrance for drug development. In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK). Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically...
February 12, 2018: Nature
https://www.readbyqxmd.com/read/29432078/endogenous-tumor-suppressor-microrna-193b-therapeutic-and-prognostic-value-in-acute-myeloid-leukemia
#10
Raj Bhayadia, Kathrin Krowiorz, Nadine Haetscher, Razan Jammal, Stephan Emmrich, Askar Obulkasim, Jan Fiedler, Adrian Schwarzer, Arefeh Rouhi, Michael Heuser, Susanne Wingert, Sabrina Bothur, Konstanze Döhner, Tobias Mätzig, Michelle Ng, Dirk Reinhardt, Hartmut Döhner, C Michel Zwaan, Marry van den Heuvel Eibrink, Dirk Heckl, Maarten Fornerod, Thomas Thum, R Keith Humphries, Michael A Rieger, Florian Kuchenbauer, Jan-Henning Klusmann
Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo...
February 12, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29431699/combined-braf-egfr-and-mek-inhibition-in-patients-with-brafv600e-mutant-colorectal-cancer
#11
Ryan B Corcoran, Thierry Andre, Chloe E Atreya, Jan H M Schellens, Takayuki Yoshino, Johanna C Bendell, Antoine Hollebecque, Autumn J McRee, Salvatore Siena, Gary Middleton, Kei Muro, Michael S Gordon, Josep Tabernero, Rona Yaeger, Peter J O'Dwyer, Yves Humblet, Filip De Vos, A Scott Jung, Jan C Brase, Savina Jaeger, Severine Bettinger, Bijoyesh Mookerjee, Fatima Rangwala, Eric Van Cutsem
Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only ~5% with BRAFV600E colorectal cancer (CRC) respond. Preclinical studies suggest that lack of efficacy in BRAFV600E CRC is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E CRC...
February 5, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29431697/convergent-therapeutic-strategies-to-overcome-the-heterogeneity-of-acquired-resistance-in-brafv600e-colorectal-cancer
#12
Mehlika Hazar-Rethinam, Marianna Kleyman, G Celine Han, David Liu, Leanne G Ahronian, Heather A Shahzade, Lifeng Chen, Aparna R Parikh, Jill N Allen, Jeffrey W Clark, Eunice L Kwak, Jason E Faris, Janet E Murphy, Theodore S Hong, Emily E Van Seventer, Brandon Nadres, Catriona B Hong, Joseph M Gurski, Nicholas A Jessop, Dora Dias-Santagata, A John Iafrate, Eliezer M Van Allen, Ryan B Corcoran
Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from BRAFV600E colorectal cancer patients receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a novel pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo...
February 5, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29431672/erk-inhibition-a-new-front-in-the-war-against-mapk-pathway-driven-cancers
#13
Inna Smalley, Keiran S M Smalley
ERK inhibitors have enormous therapeutic potential against tumors that are BRAF mutant, BRAF-MEK inhibitor resistant, or RAS mutant. In this issue of Cancer Discovery, Sullivan and colleagues report on the first-in-human dose-escalation study of the ERK inhibitor ulixertinib, which they show to be well tolerated with clinical activity against a wide range of tumor types. Cancer Discov; 8(2); 140-2. ©2018 AACR.See related article by Sullivan et al., p. 184.
February 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29430633/phacomatosis-pigmentokeratotica-a-case-of-hras-mosaicism-causing-rhabdomyosarcoma
#14
M Prieto-Barrios, R Llamas-Martin, V Velasco-Tamariz, A Calleja-Algarra, Y Ruano, P L Ortiz-Romero, J L Rodriguez-Peralto
A 17-year-old male presented with a large sebaceous naevus (SN) comprising part of his left face and scalp and a speckled lentiginous naevus (SLN) on his right trunk, hip, neck and scalp with a checkerboard pattern. His right oral hemimucosa showed extensive papillomatous lesions which were contiguous to the upper lip SN lesions. As for extracutaneous manifestations he suffered from cardiac, musculoskeletal and ocular alterations. On the other hand, he developed two primary rhabdomyosarcomas. DNA samples of the SN, SLN, the oral papillomatous hyperplasia and both rhabdomyosarcomas were analyzed by Sanger sequencing...
February 12, 2018: British Journal of Dermatology
https://www.readbyqxmd.com/read/29426295/preclinical-evaluation-and-reverse-phase-protein-array-based-profiling-of-pi3k-and-mek-inhibitors-in-endometrial-carcinoma-in-vitro
#15
Ozlem Aslan, Mattia Cremona, Clare Morgan, Lydia W Cheung, Gordon B Mills, Bryan T Hennessy
BACKGROUND: The phosphoinositide-3-kinase (PI3K) pathway is the most commonly activated pathway in cancers due to mutations at multiple nodes and loss of PTEN. Furthermore, in endometrial cancer (EC), PI3K and RAS/RAF/MEK/MAPK (RAS/MAPK herein) pathway mutations frequently co-exist. We examined the role of PI3K and RAS/MAPK pathway mutations in determining responsiveness to therapies targeted to these pathways in vitro in EC. METHODS: 13 EC cell lines were profiled for their PI3K pathway and KRAS mutational and PTEN protein status and treated with one MEK- and two PI3K- targeted inhibitors alone and in combination...
February 9, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29425910/neuroprotective-effects-of-tongxinluo-on-focal-cerebral-ischemia-and-reperfusion-injury-in-rats-associated-with-the-activation-of-the-mek1-2-erk1-2-p90rsk-signaling-pathway
#16
Zhonghai Yu, Min Cai, Xianting Li, Jingsi Zhang, Ting Wu, Feng Yang, Wen Zhu, Yijin Xiang, Wen Zhang, Jun Xiang, Dingfang Cai
Ischemic stroke brings a huge family and social burden. Although the reperfusion of ischemic cerebral tissue is the most important way to rescue ischemic stroke, ischemia-reperfusion (I/R) injury further results in brain damage and even lead to death. Recent studies demonstrated that Tongxinluo (TXL) helps to protect the brain against focal cerebral I/R injury in rats by reducing neuronal apoptosis, and the MEK1/2/ERK1/2/90 ribosomal S6 kinase (p90RSK) pathway may be involved in this protective effect. Therefore, our present research was designed to identify the potential mechanisms involved...
February 6, 2018: Brain Research
https://www.readbyqxmd.com/read/29423686/tgf-%C3%AE-1-regulation-of-p-jnk-and-l-type-calcium-channel-cav1-2-in-cortical-neurons
#17
Zhenning Liu, Jiangtao Sheng, Guoyi Peng, Jinhua Yang, Weiqiang Chen, Kangsheng Li
Central nervous system (CNS) diseases can cause a series of neuronal lesions, which may be improved by the anti-apoptotic neuroprotection of transforming growth factor-beta 1 (TGF-β1). In neurons, L-type Ca2+ channels (LTCC) are mainly composed of Cav1.2 subunits. Given the implication of TGF-β1 in numerous CNS diseases, we examined the neuroprotective effects of TGF-β1 on the Cav1.2 channel in the CNS. To simulate acute mechanical traumatic brain injury (TBI), we used a needle to create parallel scratches across plates, which were cultured for 9 h...
February 8, 2018: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/29423085/the-anti-rheumatic-drug-leflunomide-synergizes-with-mek-inhibition-to-suppress-melanoma-growth
#18
Kimberley Hanson, Stephen R Robinson, Karamallah Al-Yousuf, Adam E Hendry, Darren W Sexton, Victoria Sherwood, Grant N Wheeler
Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29422996/melatonin-regulates-cre-dependent-gene-transcription-underlying-osteoblast-proliferation-by-activating-src-and-pka-in-parallel
#19
Lin Tao, Yue Zhu
Several studies have indicated a relationship between melatonin and idiopathic scoliosis, including our previous work which demonstrated that melatonin can inhibit osteoblast proliferation; however, the mechanism remains unclear. Here, we utilized a MTT assay to show that melatonin significantly reduces osteoblast proliferation in a concentration-and time-dependent manner. Through a combination of techniques, including real-time PCR, MTT assays, immunofluorescence, and luciferase assays, we confirmed that melatonin-induced changes in phosphorylated cAMP response element-binding protein (CREB) reduced transcriptional activity in a melatonin receptor-dependent manner...
2018: American Journal of Translational Research
https://www.readbyqxmd.com/read/29421862/corrigendum-to-metapristone-suppresses-non-small-cell-lung-cancer-proliferation-and-metastasis-via-modulating-ras-raf-mek-mapk-signaling-pathway-biomed-pharmacother-90-2017-437-445
#20
Guirong Zheng, Zhichun Shen, Hongning Chen, Jian Liu, Kai Jiang, Lulu Fan, Lee Jia, Jingwei Shao
No abstract text is available yet for this article.
February 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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