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BRAF/MEK/ERK

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https://www.readbyqxmd.com/read/27922010/mek-inhibitors-block-growth-of-lung-tumours-with-mutations-in-ataxia-telangiectasia-mutated
#1
Michal Smida, Ferran Fece de la Cruz, Claudia Kerzendorfer, Iris Z Uras, Barbara Mair, Abdelghani Mazouzi, Tereza Suchankova, Tomasz Konopka, Amanda M Katz, Keren Paz, Katalin Nagy-Bojarszky, Markus K Muellner, Zsuzsanna Bago-Horvath, Eric B Haura, Joanna I Loizou, Sebastian M B Nijman
Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27848137/combined-braf-v600e-and-mek-blockade-for-braf-v600e-mutant-gliomas
#2
Jie Zhang, Tsun-Wen Yao, Rintaro Hashizume, Sujatmi Hariono, Krister J Barkovich, Qi-Wen Fan, Michael Prados, C David James, William A Weiss, Theodore Nicolaides
BRAF(V600E) is a common finding in glioma (about 10-60% depending on histopathologic subclassification). BRAF(V600E) monotherapy shows modest preclinical efficacy against BRAF(V600E) gliomas and also induces adverse secondary skin malignancies. Here, we examine the molecular mechanism of intrinsic resistance to BRAF(V600E) inhibition in glioma. Furthermore, we investigate BRAF(V600E)/MEK combination therapy that overcomes intrinsic resistance to BRAF(V600E) inhibitor and also prevents BRAF(V600E) inhibitor induced secondary malignancies...
November 15, 2016: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/27846720/-molecular-mechanisms-of-carcinogenesis-of-epithelial-ovarian-cancers
#3
Z Müllerová, T Müller, K Křivánková, B Vojtěšek, P Müller
BACKGROUND: Epithelial ovarian carcinomas are one of the most common causes of death among gynecologic malignancies in the Czech population. This group of tumors is characterized by considerable heterogeneity in terms of its pathogenesis and response to therapy. It is questionable whether advances in the elucidation of molecular pathogenesis of various types of epithelial ovarian carcinomas can contribute to application of personalized targeted therapy. AIMS: This work aims to summarize current knowledge on carcinogenesis and molecular basis of epithelial ovarian cancers and point out their potential applications in clinical practice...
2016: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/27816338/-adult-langerhans-cell-histiocytosis
#4
Mathilde de Menthon, Véronique Meignin, Alfred Mahr, Abdellatif Tazi
Langerhans cell histiocytosis (LCH) is a rare disease affecting both genders and can occur at any age. It often evolves through successive flares, and its severity varies from benign forms that don't require treatment to life threatening disease. Some patients have important functional impairment with psychological and social consequences and prolonged disability. LCH may affect only one organ, with uni- or multifocal involvement or be multisystem disease involving multiple organs. The organs most frequently involved are bones, lung, skin and the endocrinal system...
November 2, 2016: La Presse Médicale
https://www.readbyqxmd.com/read/27813079/the-plasma-membrane-ca-2-pump-pmca4b-inhibits-the-migratory-and-metastatic-activity-of-braf-mutant-melanoma-cells
#5
L Hegedus, T Garay, E Molnar, K Varga, A Bilecz, S Torok, R Padanyi, K Paszty, M Wolf, M Grusch, E Kallay, B Dome, W Berger, B Hegedus, A Enyedi
Oncogenic mutations of BRAF lead to constitutive ERK activity that supports melanoma cell growth and survival. While Ca(2+) signaling is a well-known regulator of tumor progression, the crosstalk between Ca(2+) signaling and the Ras-BRAF-MEK-ERK pathway is much less explored. Here we show that in BRAF mutant melanoma cells the abundance of the plasma membrane Ca(2+) ATPase isoform 4b (PMCA4b, ATP2B4) is low at baseline but markedly elevated by treatment with the mutant BRAF specific inhibitor vemurafenib. In line with these findings gene expression microarray data also shows decreased PMCA4b expression in cutaneous melanoma when compared to benign nevi...
November 4, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27791198/co-existence-of-braf-and-nras-driver-mutations-in-the-same-melanoma-cells-results-in-heterogeneity-of-targeted-therapy-resistance
#6
Marieke I G Raaijmakers, Daniel S Widmer, Apurva Narechania, Ossia Eichhoff, Sandra N Freiberger, Judith Wenzina, Phil F Cheng, Daniela Mihic-Probst, Rob Desalle, Reinhard Dummer, Mitchell P Levesque
Acquired chemotherapeutic resistance of cancer cells can result from a Darwinistic evolution process in which heterogeneity plays an important role. In order to understand the impact of genetic heterogeneity on acquired resistance and second line therapy selection in metastatic melanoma, we sequenced the exomes of 27 lesions which were collected from 3 metastatic melanoma patients treated with targeted or non-targeted inhibitors. Furthermore, we tested the impact of a second NRAS mutation in 7 BRAF inhibitor resistant early passage cell cultures on the selection of second line therapies...
October 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27765849/mutant-braf-upregulates-mcl-1-to-confer-apoptosis-resistance-that-is-reversed-by-mcl-1-antagonism-and-cobimetinib-in-colorectal-cancer
#7
Hisato Kawakami, Shengbing Huang, Krishnendu Pal, Shamit K Dutta, Debabrata Mukhopadhyay, Frank A Sinicrope
Oncogenic BRAF(V600E) mutations activate MAPK signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer. In BRAF(V600E)-mutant colorectal cancers, treatment failure may be related to BRAF(V600E)-mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAF(V600E) can upregulate anti-apoptotic MCL-1 in a gene dose-dependent manner using colorectal cancer cell lines isogenic for BRAF BRAF(V600E)-induced MCL-1 upregulation was confirmed by ectopic BRAF(V600E) expression that activated MEK/ERK signaling to phosphorylate (MCL-1(Thr163)) and stabilize MCL-1...
December 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27748799/growth-arrest-by-activated-braf-and-mek-inhibition-in-human-anaplastic-thyroid-cancer-cells
#8
Kento Kurata, Naoyoshi Onoda, Satoru Noda, Shinichiro Kashiwagi, Yuka Asano, Kosei Hirakawa, Masaichi Ohira
Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated...
October 7, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27729324/alternative-genetic-mechanisms-of-braf-activation-in-langerhans-cell-histiocytosis
#9
Rikhia Chakraborty, Thomas M Burke, Oliver A Hampton, Daniel J Zinn, Karen Phaik Har Lim, Harshal Abhyankar, Brooks Scull, Vijetha Kumar, Nipun Kakkar, David A Wheeler, Angshumoy Roy, Poulikos I Poulikakos, Miriam Merad, Kenneth L McClain, D Williams Parsons, Carl E Allen
Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing pathologic CD207+ dendritic cells with constitutively activated ERK. Mutually exclusive somatic mutations in MAPK pathway genes have been identified in approximately 75% of LCH cases, including recurrent BRAF-V600E and MAP2K1 mutations. In order to elucidate mechanisms of ERK activation in the remaining 25% of patients, we performed whole exome sequencing (WES, n=6), targeted BRAF sequencing (n=19) and/or whole transcriptome sequencing (RNA-seq, n=6) on 24 LCH patient samples lacking BRAF-V600E or MAP2K1 mutations...
October 11, 2016: Blood
https://www.readbyqxmd.com/read/27669459/sustained-erk-inhibition-maximizes-responses-of-brafv600e-thyroid-cancers-to-radioiodine
#10
James Nagarajah, Mina Le, Jeffrey A Knauf, Giuseppe Ferrandino, Cristina Montero-Conde, Nagavarakishore Pillarsetty, Alexander Bolaender, Christopher Irwin, Gnana Prakasam Krishnamoorthy, Mahesh Saqcena, Steven M Larson, Alan L Ho, Venkatraman Seshan, Nobuya Ishii, Nancy Carrasco, Neal Rosen, Wolfgang A Weber, James A Fagin
Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer...
November 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27650277/a-phase-i-dose-escalation-study-of-tak-733-an-investigational-oral-mek-inhibitor-in-patients-with-advanced-solid-tumors
#11
Alex A Adjei, Patricia LoRusso, Antoni Ribas, Jeffrey A Sosman, Anna Pavlick, Grace K Dy, Xiaofei Zhou, Esha Gangolli, Michelle Kneissl, Stephanie Faucette, Rachel Neuwirth, Viviana Bózon
Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1...
September 21, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27641727/vemurafenib-in-combination-with-cobimetinib-in-relapsed-and-refractory-extramedullary-multiple-myeloma-harboring-the-braf-v600e-mutation
#12
Ulrich J M Mey, Christoph Renner, Roger von Moos
BRAF mutations are present in a variety of cancers and cause constitutive activation of the Ras-Raf-MEK-ERK signaling pathway. In cutaneous malignant melanoma, combined treatment with BRAF and MEK inhibitors is associated with high response rates and has been shown to improve progression free as well as overall survival compared to BRAF inhibition alone. In multiple myeloma, BRAF mutations are detectable only in a minority of patients. Only few data are available regarding the clinical activity of BRAF inhibitors in BRAF-positive multiple myeloma patients, including some anecdotal reports on remarkable responses in individuals being resistant to all other available anti-myeloma treatment approaches...
September 19, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27632801/molecular-mechanisms-supporting-a-pathogenic-role-for-human-polyomavirus-6-small-t-antigen-protein-phosphatase-2a-targeting-and-mapk-cascade-activation
#13
Julie H Wu, Rebecca A Simonette, Harrison P Nguyen, Peter L Rady, Stephen K Tyring
BRAF inhibitors are highly effective therapies in treating a subset of melanomas but are associated with induction of secondary cutaneous squamous cell carcinoma (cSCC). Recently, Human Polyomavirus 6 (HPyV6) was found to actively express viral proteins in BRAF inhibitor-induced cSCCs; however, the specific cellular mechanisms by which HPyV6 may facilitate neoplastic cell growth require further investigation. The current study describes a novel pathogenic mechanism of action for HPyV6 small tumor (sT) antigen which involves binding to protein phosphatase 2A (PP2A) via its WFG motif and zinc binding sites...
September 15, 2016: Journal of Medical Virology
https://www.readbyqxmd.com/read/27597420/brafv600e-and-map2k1-mutations-in-langerhans-cell-histiocytosis-occur-predominantly-in-children
#14
Kaixuan Zeng, Koichi Ohshima, Yixiong Liu, Weichen Zhang, Lu Wang, Linni Fan, Mingyang Li, Xia Li, Zhe Wang, Shuangping Guo, Qingguo Yan, Ying Guo
Langerhans cell histiocytosis (LCH) is a proliferative disease of CD1a(+) /CD207(+) dendritic cells. Recurrent BRAFV600E and MAP2K1 mutations have been reported in LCH. To investigate the relationship among the mutation, clinical findings, and differentiation status of LCH, respectively, we studied 97 cases of LCH by using Sanger sequencing and immunohistochemistry. The mutually exclusive BRAFV600E and MAP2K1 mutation rates were 32% and 17.5%, respectively. All MAP2K1 mutations were missense mutations without any in-frame deletions; 2 new recurrent missense mutations (ie, p...
September 6, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27577079/non-v600-braf-mutations-recurrently-found-in-lung-cancer-predict-sensitivity-to-the-combination-of-trametinib-and-dabrafenib
#15
Amir Noeparast, Erik Teugels, Philippe Giron, Gil Verschelden, Sylvia De Brakeleer, Lore Decoster, Jacques De Grève
Approximately half of BRAF-mutated Non-small cell lung cancers (NSCLCs) harbor a non-V600 BRAF mutation, accounting for ~40,000 annual deaths worldwide. Recent studies have revealed the benefits of combined targeted therapy with a RAF-inhibitor (Dabrafenib) and a MEK-inhibitor (Trametinib) in treating V600 BRAF mutant cancers, including NSCLC. In contrast, sensitivity of non-V600 BRAF mutations to these inhibitors is not documented. Non-V600 mutations can either increase or impair BRAF kinase activity. However, impaired BRAF kinases can still activate the ERK pathway in a CRAF-dependent manner...
August 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27572939/gli-inhibitor-gant61-kills-melanoma-cells-and-acts-in-synergy-with-obatoclax
#16
Kateřina Vlčková, Jiri Réda, Lubica Ondrušová, Mohammad Krayem, Ghanem Ghanem, Jiri Vachtenheim
MEK kinase inhibitors (trametinib and selumetinib) or kinase inhibitors directed against mutated BRAF(V600E) (vemurafenib and dabrafenib) have initial encouraging effects in the treatment of melanoma but acquired resistance appears almost invariably after some months. Studies revealed mutually exclusive NRAS and BRAF activating mutations driving the MAPK/ERK pathway among human melanomas. Although combination therapy exerts significantly better antitumor cell efficacy, complete remission is rarely achieved...
September 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27554081/braf-v600e-mutation-in-hairy-cell-leukemia-from-bench-to-bedside
#17
Brunangelo Falini, Maria Paola Martelli, Enrico Tiacci
Hairy cell leukemia (HCL) is a distinct clinicopathological entity whose underlying genetic lesion has remained a mystery for over half a century. The BRAF V600E mutation is now recognized as the causal genetic event of HCL because it is somatic, present in the entire tumor clone, detectable in almost all cases at diagnosis (encompassing the whole disease spectrum), and stable at relapse. BRAF V600E leads to the constitutive activation of the RAF-MEK-extracellular signal-regulated kinase (ERK) signaling pathway which represents the key event in the molecular pathogenesis of HCL...
October 13, 2016: Blood
https://www.readbyqxmd.com/read/27545456/synergistic-effects-of-ion-transporter-and-map-kinase-pathway-inhibitors-in-melanoma
#18
Ugur Eskiocak, Vijayashree Ramesh, Jennifer G Gill, Zhiyu Zhao, Stacy W Yuan, Meng Wang, Travis Vandergriff, Mark Shackleton, Elsa Quintana, Timothy M Johnson, Ralph J DeBerardinis, Sean J Morrison
New therapies are required for melanoma. Here, we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human melanoma cells than normal human cells. This reflects on-target inhibition of the ATP1A1 Na(+)/K(+) pump, which is highly expressed by melanoma. MEK inhibitor and/or BRAF inhibitor additively or synergistically combined with digitoxin to induce cell death, inhibiting growth of patient-derived melanomas in NSG mice and synergistically extending survival...
2016: Nature Communications
https://www.readbyqxmd.com/read/27538133/-expression-of-mek-erk-signal-pathways-in-renal-cell-carcinoma-with-bone-metastasis
#19
C P Qin, C L Liu, Y H Zhao, H Q Yin, Y Q DU, F Z Hu, Z Z Sheng, T Xu
OBJECTIVE: To investigate the expression of MEK/ERK signaling pathways in renal cell carcinoma with bone metastasis, and to analyze the differences of expressions of VEGFR-2, MEK, ERK on the primary and metastasis tissue and its mechanism. METHODS: The tissue samples were obtained from 7 renal cell carcinoma patients kindly provided by Department of Urology, Peking University People's Hospital from January 1, 2009 to January 1, 2010. The expression of MEK/ERK signaling pathways was detected in the 7 renal cell carcinoma patients` primary and matched metastatic tissues with ICH, The antibody concentrations were 1:200, 1:25, and 1:250, respectively...
February 18, 2016: Beijing da Xue Xue Bao. Yi Xue Ban, Journal of Peking University. Health Sciences
https://www.readbyqxmd.com/read/27476449/cutaneous-wound-healing-through-paradoxical-mapk-activation-by-braf-inhibitors
#20
Helena Escuin-Ordinas, Shuoran Li, Michael W Xie, Lu Sun, Willy Hugo, Rong Rong Huang, Jing Jiao, Felipe Meira de-Faria, Susan Realegeno, Paige Krystofinski, Ariel Azhdam, Sara Marie D Komenan, Mohammad Atefi, Begoña Comin-Anduix, Matteo Pellegrini, Alistair J Cochran, Robert L Modlin, Harvey R Herschman, Roger S Lo, William H McBride, Tatiana Segura, Antoni Ribas
BRAF inhibitors are highly effective therapies for the treatment of BRAF(V600)-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression...
2016: Nature Communications
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