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https://www.readbyqxmd.com/read/29454854/erk1-2-inhibitors-new-weapons-to-inhibit-the-ras-regulated-raf-mek1-2-erk1-2-pathway
#1
REVIEW
Andrew M Kidger, James Sipthorp, Simon J Cook
The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is de-regulated in a variety of cancers due to mutations in receptor tyrosine kinases (RTKs), negative regulators of RAS (such as NF1) and core pathway components themselves (RAS, BRAF, CRAF, MEK1 or MEK2). This has driven the development of a variety of pharmaceutical agents to inhibit RAF-MEK1/2-ERK1/2 signalling in cancer and both RAF and MEK inhibitors are now approved and used in the clinic. There is now much interest in targeting at the level of ERK1/2 for a variety of reasons...
February 15, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29431697/convergent-therapeutic-strategies-to-overcome-the-heterogeneity-of-acquired-resistance-in-brafv600e-colorectal-cancer
#2
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
#3
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/29413908/melanoma-metabolism-contributes-to-the-cellular-responses-to-mapk-erk-pathway-inhibitors
#4
REVIEW
Philippe Marchetti, Anne Trinh, Raeeka Khamari, Jerome Kluza
BACKGROUND: Besides its influence on survival, growth, proliferation, invasion and metastasis, cancer cell metabolism also greatly influences the cellular responses to molecular-targeted therapies. SCOPE OF THE REVIEW: To review the recent advances in elucidating the metabolic effects of BRAF and MEK inhibitors (clinical inhibitors of the MAPK/ERK pathway) in melanoma and discuss the underlying mechanisms involved in the way metabolism can influence melanoma cell death and resistance to BRAF and MEK inhibitors...
January 31, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29363351/mitogen-activated-protein-kinase-mek-inhibitors-to-treat-melanoma-alone-or-in-combination-with-other-kinase-inhibitors
#5
Elnaz Faghfuri, Shekoufeh Nikfar, Kamal Niaz, Mohammad Ali Faramarzi, Mohammad Abdollahi
Malignant melanoma (MM) is an aggressive disease with a rapidly rising incidence due to neoplasm of melanocytes. Molecular targeted therapies have demonstrated lower toxicity and improved overall survival versus conventional therapies of MM. The revealing of mutations in the BRAF/MEK/ERK pathway has led to the development of BRAF inhibitors such as vemurafenib and dabrafenib for the treatment of cutaneous MM. Though, progression of resistance to these agents has prompted attempts to target downstream proteins in this pathway...
January 24, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29348459/distinct-dependencies-on-receptor-tyrosine-kinases-in-the-regulation-of-mapk-signaling-between-braf-v600e-and-non-v600e-mutant-lung-cancers
#6
Hiroshi Kotani, Yuta Adachi, Hidenori Kitai, Shuta Tomida, Hideaki Bando, Anthony C Faber, Takayuki Yoshino, Dominic C Voon, Seiji Yano, Hiromichi Ebi
BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells...
January 19, 2018: Oncogene
https://www.readbyqxmd.com/read/29320991/an-oncogenic-mutant-of-rheb-rheb-y35n-exhibits-an-altered-interaction-with-braf-resulting-in-cancer-transformation
#7
Jeffrey J Heard, Ivy Phung, Mark I Potes, Fuyuhiko Tamanoi
BACKGROUND: RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB...
January 10, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29311225/keeping-tumors-out-of-the-mapk-fitness-zone
#8
David F Stern
Greatest fitness of tumor cell subclones in patients undergoing MAPK-targeting therapies requires just-right levels of MAPK pathway signaling. New therapeutic approaches induce tumor cell death by intensifying MAPK signaling induced by inhibitor withdrawal in combination with DNA damage, or prevent selection of resistant clones with a steep fitness barrier imposed by triple combination of BRAF, MEK, and ERK inhibitors. Cancer Discov; 8(1); 20-3. ©2018 AACRSee related article by Hong et al., p. 74.
January 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29259016/oncogenic-ras-induced-perinuclear-signaling-complexes-requiring-ksr1-regulate-signal-transmission-to-downstream-targets
#9
Sandip K Basu, Sook Lee, Jacqueline Salotti, Srikanta Basu, Krisada Sakchaisri, Zhen Xiao, Vijay Walia, Christopher J Westlake, Deborah K Morrison, Peter F Johnson
The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here we show that oncogenic RAS and BRAF induce perinuclear re-localization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2α co-localizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population...
December 19, 2017: Cancer Research
https://www.readbyqxmd.com/read/29233910/targeting-cdk1-and-mek-erk-overcomes-apoptotic-resistance-in-braf-mutated-human-colorectal-cancer
#10
Peng Zhang, Hisato Kawakami, Weizhen Liu, Xiangyu Zeng, Klaus Strebhardt, Kaixiong Tao, Shengbing Huang, Frank A Sinicrope
The BRAFV600E mutation occurs in ~8% of human colorectal cancers (CRCs) and is associated with therapeutic resistance that is due, in part, to re-activation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human BRAFV600E CRCs. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAFV600E CRC cells. BRAFV600E CRC cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1,2,5,9 inhibitor)...
December 12, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29229605/mir-204-5p-and-mir-211-5p-contribute-to-braf-inhibitor-resistance-in-melanoma
#11
Marta Díaz-Martínez, Lucía Benito-Jardón, Lola Alonso, Lisa Koetz-Ploch, Eva Hernando, Joaquin Teixido
Melanoma treatment with the BRAF V600E inhibitor vemurafenib (VMF) provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to VMF with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in VMF-resistant cells was determined to impact VMF response. Their expression was rapidly affected by VMF treatment through RNA stabilization...
December 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/29196297/acetylsalicylic-acid-governs-the-effect-of-sorafenib-in-ras-mutant-cancers
#12
Heinz Hammerlindl, Dinoop Ravindran Menon, Sabrina Hammerlindl, Abdullah Al Emran, Joachim Torrano, Katrin Sproesser, Divya Thakkar, Min Xiao, Victoria G Atkinson, Brian Gabrielli, Nikolas K Haass, Meenhard Herlyn, Clemens Krepler, Helmut Schaider
PURPOSE: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult to treat RAS-mutant cancer. EXPERIMENTAL DESIGN: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro. The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown...
December 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29193645/mapk-inhibitors-induce-serine-peptidase-inhibitor-kazal-type-1-spink1-secretion-in-braf-v600e-mutant-colorectal-adenocarcinoma
#13
Kati Räsänen, Kien X Dang, Harri Mustonen, Tho H Ho, Susanna Lintula, Hannu Koistinen, Ulf-Håkan Stenman, Caj Haglund, Jakob Stenman
The mitogen-activated protein kinase (MAPK) pathway plays a central role in colorectal cancers (CRC). In particular, BRAF V600E-mutant tumors, which represent around 10% of CRCs, are refractory to current therapies. Over-expression and secretion of serine peptidase inhibitor Kazal type 1 (SPINK1) is observed in around 50% of CRCs and its serum level can be used as a biomarker for poor prognosis. Utilizing a recently developed Extendable Blocking Probe assay, we analyzed the BRAF mutation status in a CRC patient cohort (N=571) using tissue-derived RNA as the starting material...
November 28, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29180761/combined-inhibition-of-mek-and-nuclear-erk-translocation-has-synergistic-antitumor-activity-in-melanoma-cells
#14
Rand Arafeh, Karen Flores, Alona Keren-Paz, Galia Maik-Rachline, Naomi Gutkind, Steven Rosenberg, Rony Seger, Yardena Samuels
Genetic alterations in BRAF, NRAS and NF1 that activate the ERK cascade, account for over 80% of metastatic melanomas. However, ERK cascade inhibitors have been proven beneficial almost exclusively for BRAF mutant melanomas. One of the hallmarks of the ERK cascade is the nuclear translocation of ERK1/2, which is important mainly for the induction of proliferation. This translocation can be inhibited by the NTS-derived peptide (EPE) that blocks the ERK1/2-importin7 interaction, inhibits the nuclear translocation of ERK1/2, and arrests active ERK1/2 in the cytoplasm...
November 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29171936/braf-internal-deletions-and-resistance-to-braf-mek-inhibitor-therapy
#15
Douglas B Johnson, Merrida A Childress, Zachary R Chalmers, Garrett M Frampton, Siraj M Ali, Samuel M Rubinstein, David Fabrizio, Jeffrey S Ross, Sohail Balasubramanian, Vincent A Miller, Philip J Stephens, Jeffrey A Sosman, Christine M Lovly
BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV600 - mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pre-treatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAFV600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2-8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling...
November 24, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29167314/wnt-%C3%AE-catenin-pathway-activation-mediates-adaptive-resistance-to-braf-inhibition-in-colorectal-cancer
#16
Guangming Chen, Chenxi Gao, Xuan Gao, Dennis Han Zhang, Shih-Fan Kuan, Timothy F Burns, Jing Hu
One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC). While many studies on BRAF inhibitor resistance in CRC have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on CRC resistance to BRAF inhibition...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29107340/langerhans-cell-histiocytosis-a-neoplastic-disorder-driven-by-ras-erk-pathway-mutations
#17
REVIEW
Gary Tran, Thy N Huynh, Amy S Paller
Langerhans cell histiocytosis (LCH) is a disorder of myeloid neoplasia of dendritic cells that affects 1 in 200,000 children <15 years of age and even fewer adults. LCH presents with a spectrum of clinical manifestations. High-risk stratification is reserved for infiltration of blood, spleen, liver, and lungs. After decades of debate on the disease pathogenesis, a neoplastic mechanism is now favored on the basis of LCH cell clonality, rare cases of familial clustering, and recent evidence of mutations involving the Ras/Raf/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase) pathway in lesional biopsy specimens...
October 26, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/29100280/impact-of-phosphoinositide-3-kinase-and-vitamin-d3-nuclear-receptor-single-nucleotide-polymorphisms-on-the-outcome-of-malignant-melanoma-patients
#18
Francesca Morgese, Davide Soldato, Silvia Pagliaretta, Riccardo Giampieri, Donatella Brancorsini, Mariangela Torniai, Silvia Rinaldi, Agnese Savini, Azzurra Onofri, Marina Scarpelli, Rossana Berardi
Background: Several studies associating single nucleotide polymorphisms (SNPs) frequencies with tumors outcome have been conducted, nevertheless malignant melanoma literature data are inconclusive.Therefore we evaluate the impact of different genotypes for phosphoinositide-3-kinase (PI3K) and vitamin D3 nuclear receptor (VDR) SNPs on melanoma patients' outcome. Materials and methods: Genomic DNA of 88 patients was extracted from blood and tumor samples. SNPs were determined by PCR using TaqMan assays...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29094484/degradation-of-ampk-%C3%AE-1-sensitizes-braf-inhibitor-resistant-melanoma-cells-to-arginine-deprivation
#19
Ying-Ying Li, Chunjing Wu, Sumedh S Shah, Shu-Mei Chen, Medhi Wangpaichitr, Macus T Kuo, Lynn G Feun, Xiaoqing Han, Miguel Suarez, Jeffrey Prince, Niramol Savaraj
Melanomas harboring BRAF mutation (V600E) are known to recur frequently following treatment with BRAF inhibitors (BRAFi) despite a high initial response rate. Our previous study has uncovered that BRAFi-resistant melanoma (BR) cells are vulnerable to arginine deprivation. It has been reported that naïve melanoma cells undergo autophagy and re-express argininosuccinate synthetase 1 (ASS1) to enable them to synthesize arginine for survival when encountering arginine deprivation. Abolishing these two factors in BR cells confers sensitivity to arginine deprivation...
November 2, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29070145/-effect-of-erk1-2-signaling-pathway-inhibitor-pd98059-on-the-expression-of-ras-braf-mek-erk1-2-in-marrow-nucleated-red-blood-cells-of-cms-patients
#20
Yuan-Fang Han, Lin-Hua Ji, Ting-Ting Feng, Fang Liu, Sen Cui, Juan Su
OBJECTIVE: To investigate the effect of ERK1 / 2 signaling pathway inhibitor PD98059 on Ras, Raf, MEK, ERK1, ERK2 expression in order to explore a new way for basic research and clinical treatment of the chronic mountain sickness(CMS). METHODS: Sixteen CMS patients were selected, the bone marrow was collected for isolation of monomuclear cells (MNC), the cells were sorted by using CD71 and CD235a antibody magnetic beads, then positive cells were diveded into 5 groups: blank control, DMSO and PD98059 5, 10 and 20 µmol/L, and were cultured in hypoxid condition for 72 hours...
October 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
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