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https://www.readbyqxmd.com/read/28620782/role-of-key-genetic-mutations-on-increasing-migration-of-brain-cancer-cells-through-confinement
#1
Loan Bui, Sayem H Bhuiyan, Alissa Hendrick, Cheng-Jen Chuong, Young-Tae Kim
Uncontrolled invasive cancer cell migration is among the major challenges for the treatment and management of brain cancer. Although the genetic profiles of brain cancer cells have been well characterized, the relationship between the genetic mutations and the cells' mobility has not been clearly understood. In this study, using microfluidic devices that provide a wide range of physical confinements from 20 × 5 μm(2) to 3 × 5 μm(2) in cross sections, we studied the effect of physical confinement on the migratory capacity of cell lines with different types of mutations...
September 2017: Biomedical Microdevices
https://www.readbyqxmd.com/read/28620126/impact-of-phosphoinositide-3-kinase-and-vitamin-d3-nuclear-receptor-single-nucleotide-polymorphisms-on-the-outcome-of-malignant-melanoma-patients
#2
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...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28596940/histone-deacetylase-inhibitor-treatment-increases-the-expression-of-the-plasma-membrane-ca-2-pump-pmca4b-and-inhibits-the-migration-of-melanoma-cells-independent-of-erk
#3
Luca Hegedüs, Rita Padányi, Judit Molnár, Katalin Pászty, Karolina Varga, István Kenessey, Eszter Sárközy, Matthias Wolf, Michael Grusch, Zoltán Hegyi, László Homolya, Clemens Aigner, Tamás Garay, Balázs Hegedüs, József Tímár, Enikö Kállay, Ágnes Enyedi
Several new therapeutic options emerged recently to treat metastatic melanoma; however, the high frequency of intrinsic and acquired resistance among patients shows a need for new therapeutic options. Previously, we identified the plasma membrane Ca(2+) ATPase 4b (PMCA4b) as a metastasis suppressor in BRAF-mutant melanomas and found that mutant BRAF inhibition increased the expression of the pump, which then inhibited the migratory and metastatic capability of the cells. Earlier it was also demonstrated that histone deacetylase inhibitors (HDACis) upregulated PMCA4b expression in gastric, colon, and breast cancer cells...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28595656/ros-production-induced-by-braf-inhibitor-treatment-rewires-metabolic-processes-affecting-cell-growth-of-melanoma-cells
#4
Giulia Cesi, Geoffroy Walbrecq, Andreas Zimmer, Stephanie Kreis, Claude Haan
BACKGROUND: Most melanoma patients with BRAF(V600E) positive tumors respond well to a combination of BRAF kinase and MEK inhibitors. However, some patients are intrinsically resistant while the majority of patients eventually develop drug resistance to the treatment. For patients insufficiently responding to BRAF and MEK inhibitors, there is an ongoing need for new treatment targets. Cellular metabolism is such a promising new target line: mutant BRAF(V600E) has been shown to affect the metabolism...
June 8, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28594589/mek-inhibitors-in-oncology-a-patent-review-2015-present
#5
Debarshi Kar Mahapatra, Vivek Asati, Sanjay Kumar Bharti
The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways have been identified as promising therapeutic targets for cancer therapy. Over-activation of these pathways and their components including gene mutations has been considered as one of the major causes of melanoma. Mitogen-activated protein kinase (MEK) is a downstream kinase of RAS pathway found in two different forms MEK1/2. The MEK inhibitors in combination with other kinase/mutant gene inhibitors have shown promising results in patients with metastatic melanoma...
June 19, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28551618/mek162-enhances-antitumor-activity-of-5-fluorouracil-and-trifluridine-in-kras-mutated-human-colorectal-cancer-cell-lines
#6
Jun Gong, Yuan Chen, Lixin Yang, Raju Pillai, Senji Shirasawa, Marwan Fakih
BACKGROUND: Preclinical evidence demonstrates that mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway inhibition increases sensitivity to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines and xenografts. Here, we aimed to investigate how CRC cell sensitivity to this combination is correlated to Kirsten rat sarcoma (KRAS) and proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) mutation, that are common in CRC and often lead to resistance to chemotherapy...
June 2017: Anticancer Research
https://www.readbyqxmd.com/read/28551613/erdheim-chester-disease-comprehensive-review-of-molecular-profiling-and-therapeutic-advances
#7
REVIEW
Faysal Haroun, Kristen Millado, Imad Tabbara
The revised 2016 World Health Organization classification introduced Erdheim-Chester disease (ECD) as a provisional entity within the histiocytic and dendritic cell neoplasms separate from the juvenile xanthogranuloma family based on distinct molecular features. However, evolving knowledge regarding the molecular and genetic aberrations in addition to common clinical features of ECD support the classification of ECD together with Langerhans cell histiocytosis (LCH). Accordingly, ECD can be thought of as an inflammatory myeloid clonal disorder based on the detection of various activating mutations along the mitogen activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) pathway with most notable variant being a valine to a glutamic acid substitution at amino acid 600 in the B-rapidly accelerated fibrosarcoma protein (BRAFV600E)...
June 2017: Anticancer Research
https://www.readbyqxmd.com/read/28550040/kras-g12d-expression-in-lung-resident-myeloid-cells-promotes-pulmonary-lch-like-neoplasm-sensitive-to-statin-treatment
#8
Tamihiro Kamata, Susan Giblett, Catrin Pritchard
Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm associated with somatic mutations in the genes involved in the RAF/MEK/ERK signaling pathway. Recently, oncogenic mutations in NRAS/KRAS, upstream regulators of the RAF/MEK/ERK pathway, have been reported in pulmonary, but not in non-pulmonary, LCH cases, suggesting organ-specific contribution of oncogenic RAS to LCH pathogenesis. Using a mouse model expressing KRAS(G12D) in the lung by nasal delivery of adenoviral Cre, here we show that KRAS(G12D) expression in lung-resident myeloid cells induces pulmonary LCH-like neoplasms comprised of pathogenic CD11c(high)F4/80+CD207+ cells...
May 26, 2017: Blood
https://www.readbyqxmd.com/read/28537912/braf-mek-inhibitors-promote-cd47-expression-that-is-reversible-by-erk-inhibition-in-melanoma
#9
Fen Liu, Chen Chen Jiang, Xu Guang Yan, Hsin-Yi Tseng, Chun Yan Wang, Yuan Yuan Zhang, Hamed Yari, Ting La, Margaret Farrelly, Su Tang Guo, Rick F Thorne, Lei Jin, Qi Wang, Xu Dong Zhang
The expression of CD47 on the cancer cell surface transmits "don't eat me" signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation of CD47 through nuclear respiratory factor 1 (NRF-1) in melanoma cells. Treatment with BRAF/MEK inhibitors upregulated CD47 in cultured melanoma cells and fresh melanoma isolates. Similarly, melanoma cells selected for resistance to the BRAF inhibitor vemurafenib expressed higher levels of CD47...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28512266/activating-mapk1-erk2-mutation-in-an-aggressive-case-of-disseminated-juvenile-xanthogranuloma
#10
Rikhia Chakraborty, Oliver A Hampton, Harshal Abhyankar, Daniel J Zinn, Amanda Grimes, Brooks Skull, Olive Eckstein, Nadia Mahmood, David A Wheeler, Dolores Lopez-Terrada, Tricia L Peters, John M. Hicks, Tarek Elghetany, Robert Krance, Poulikos I Poulikakos, Miriam Merad, Kenneth L McClain, Carl E Allen, Donald W. Parsons
Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder that is usually benign and self-limiting. We present a case of atypical, aggressive JXG harboring a novel mitogen-activated protein kinase (MAPK) pathway mutation in the MAPK1 gene, which encodes mitogen-activated protein kinase 1 or extracellular signal-regulated 2 (ERK2). Our analysis revealed that the mutation results in constitutive ERK activation that is resistant to BRAF or MEK inhibitors but susceptible to an ERK inhibitor. These data highlight the importance of identifying specific MAPK pathway alterations as part of the diagnostic workup for patients with histiocytic disorders rather than initiating empiric treatment with MEK inhibitors...
April 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28504689/molecular-signaling-in-multiple-myeloma-association-of-ras-raf-mutations-and-mek-erk-pathway-activation
#11
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/28473531/oncogenic-ras-regulates-long-non-coding-rna-orilnc1-in-human-cancer
#12
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/28407239/the-therapeutic-potential-of-targeting-the-braf-mutation-in-patients-with-colorectal-cancer
#13
REVIEW
Afsane Bahrami, AmirReza Hesari, Majid Khazaei, Seyed Mahdi Hassanian, Gordon A 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/28404629/braf-signaling-principles-unveiled-by-large-scale-human-mutation-analysis-with-a-rapid-lentivirus-based-gene-replacement-method
#14
Chae-Seok Lim, Xi Kang, Vincent Mirabella, Huaye Zhang, Qian Bu, Yoichi Araki, Elizabeth T Hoang, Shiqiang Wang, Ying Shen, Sukwoo Choi, Bong-Kiun Kaang, Qiang Chang, Zhiping P Pang, Richard L Huganir, J Julius Zhu
Rapid advances in genetics are linking mutations on genes to diseases at an exponential rate, yet characterizing the gene mutation-cell behavior relationships essential for precision medicine remains a daunting task. More than 350 mutations on small GTPase BRaf are associated with various tumors, and ∼40 mutations are associated with the neurodevelopmental disorder cardio-facio-cutaneous syndrome (CFC). We developed a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and ∼50 disease-linked BRaf mutants, including all CFC-linked mutants...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28396940/adjunction-of-a-mek-inhibitor-to-vemurafenib-in-the-treatment-of-metastatic-melanoma-results-in-a-60-reduction-of-acute-kidney-injury
#15
Cécile Teuma, Solenne Pelletier, Mona Amini-Adl, Marie Perier-Muzet, Delphine Maucort-Boulch, Luc Thomas, Maurice Laville, Denis Fouque, Stéphane Dalle
INTRODUCTION: A combined therapy MEK inhibitor, Cobimetinib (CB) and BRAF inhibitor, Vemurafenib (VMF), results in an improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma. VMF skin adverse effects attributed to ERK paradoxical activation are decreased by the adjunction of CB. The aim of this study was to determine if this combination also improved the renal side effects of VMF. PATIENTS AND METHODS: To investigate the incidence of acute kidney injury (AKI), we conducted a retrospective observational monocentric study in Lyon Sud University Hospital in France...
May 2017: Cancer Chemotherapy and Pharmacology
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
#16
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 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28297625/genomics-of-hairy-cell-leukemia
#17
Enrico Tiacci, Valentina Pettirossi, Gianluca Schiavoni, Brunangelo Falini
Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with unique clinicopathologic features and an initial exquisite sensitivity to chemotherapy with purine analogs; however, the disease relapses, often repeatedly. The enigmatic pathogenesis of HCL was recently clarified by the discovery of its underlying genetic cause, the BRAF-V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF-V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior...
March 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28282860/strategies-for-overcoming-resistance-in-tumours-harboring-braf-mutations
#18
REVIEW
Nourah Mohammad Obaid, Karen Bedard, Weei-Yuarn Huang
The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of the BRAF gene. Since the initial identification of the BRAF mutation in 2002, a series of small molecular inhibitors that target the BRAFV600E have been developed, but intrinsic and acquired resistance to these drugs has presented an ongoing challenge...
March 8, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28270557/raf1-braf-dimerization-integrates-the-signal-from-ras-to-erk-and-rok%C3%AE
#19
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/28194436/real-time-genomic-profiling-of-histiocytoses-identifies-early-kinase-domain-braf-alterations-while-improving-treatment-outcomes
#20
Lynn H Lee, Anjelika Gasilina, Jayeeta Roychoudhury, Jason Clark, Francis X McCormack, Joseph Pressey, Michael S Grimley, Robert Lorsbach, Siraj Ali, Mark Bailey, Philip Stephens, Jeffrey S Ross, Vincent A Miller, Nicolas N Nassar, Ashish R Kumar
Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing...
February 9, 2017: JCI Insight
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