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https://www.readbyqxmd.com/read/28527005/erratum-to-rapid-progression-of-intracranial-melanoma-metastases-controlled-with-combined-braf-mek-inhibition-after-discontinuation-of-therapy-a-clinical-challenge
#1
Daniel N Cagney, Brian M Alexander, F Stephen Hodi, Elizabeth I Buchbinder, Patrick A Ott, Ayal A Aizer
No abstract text is available yet for this article.
May 19, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28526719/management-of-treatment-related-adverse-events-with-agents-targeting-the-mapk-pathway-in-patients-with-metastatic-melanoma
#2
Adil Daud, Katy Tsai
Tremendous progress has been made in the clinical landscape of advanced-stage BRAF V600-mutant melanoma treatment over the past 5 years. Targeted therapies that inhibit specific steps of the mitogen-activated protein kinase pathway have been shown to provide significant overall treatment benefit in patients with this difficult-to-treat disease. Combination therapy with BRAF and MEK inhibitors (dabrafenib plus trametinib or vemurafenib plus cobimetinib, respectively) has become standard of care. These agents are administered until disease progression or unacceptable toxicity occurs; thus, some patients may remain on maintenance therapy for an extended period of time, while toxicities may result in early discontinuation in other patients...
May 18, 2017: Oncologist
https://www.readbyqxmd.com/read/28513992/immunoregulatory-protein-b7-h3-promotes-growth-and-decreases-sensitivity-to-therapy-in-metastatic-melanoma-cells
#3
Karine Flem-Karlsen, Christina Tekle, Yvonne Andersson, Kjersti Flatmark, Øystein Fodstad, Caroline E Nunes-Xavier
B7-H3 (CD276) belongs to the B7-family of immunoregulatory proteins, and has been implicated in cancer progression and metastasis. In this study, we found that metastatic melanoma cells with knockdown expression of B7-H3 showed modest decrease in proliferation and glycolytic capacity, and were more sensitive to dacarbazine (DTIC) chemotherapy and small-molecule inhibitors targeting MAP kinase (MAPK)- and AKT/mTOR-pathways: vemurafenib (PLX4032; BRAF inhibitor), binimetinib (MEK-162; MEK inhibitor), everolimus (RAD001; mTOR inhibitor) and triciribidine (API-2; AKT inhibitor)...
May 17, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28512266/activating-mapk1-erk2-mutation-in-an-aggressive-case-of-disseminated-juvenile-xanthogranuloma
#4
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, M John Hicks, Tarek Elghetany, Robert Krance, Poulikos I Poulikakos, Miriam Merad, Kenneth L McClain, Carl E Allen, Donald Williams 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/28512244/engineering-and-functional-characterization-of-fusion-genes-identifies-novel-oncogenic-drivers-of-cancer
#5
Hengyu Lu, Nicole Villafane, Turgut Dogruluk, Caitlin L Grzeskowiak, Kathleen Kong, Yiu Huen Tsang, Oksana Zagorodna, Angeliki Pantazi, Lixing Yang, Nicholas J Neill, Young Won Kim, Chad J Creighton, Roel G Verhaak, Gordon B Mills, Peter Park, Raju S Kucherlapati, Kenneth L Scott
Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in TCGA datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28504689/molecular-signaling-in-multiple-myeloma-association-of-ras-raf-mutations-and-mek-erk-pathway-activation
#6
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/28504036/combination-therapy-of-braf-inhibitors-for-advanced-melanoma-with-braf-v600-mutation-a-systematic-review-and-meta-analysis
#7
Siin Kim, Hyung Tae Kim, Hae Sun Suh
BACKGROUND: Although BRAF inhibitors have been used to treat advanced melanoma with BRAF mutation, combination strategies are suggested due to acquired resistance to BRAF inhibitors. OBJECTIVE: To assess the efficacy of BRAF inhibitor-based combination therapy for the treatment of advanced melanoma with BRAF mutation. METHODS: We conducted a systematic review and meta-analysis of studies that compared BRAF inhibitor-based combination therapy with BRAF inhibitor monotherapy...
May 15, 2017: Journal of Dermatological Treatment
https://www.readbyqxmd.com/read/28503307/clinical-significance-of-intronic-variants-in-braf-inhibitor-resistant-melanomas-with-altered-braf-transcript-splicing
#8
Gulietta M Pupo, Suzanah C Boyd, Carina Fung, Matteo S Carlino, Alexander M Menzies, Bernadette Pedersen, Peter Johansson, Nicholas K Hayward, Richard F Kefford, Richard A Scolyer, Georgina V Long, Helen Rizos
Alternate BRAF splicing is the most common mechanism of acquired resistance to BRAF inhibitor treatment in melanoma. Recently, alternate BRAF exon 4-8 splicing was shown to involve an intronic mutation, located 51 nucleotides upstream of BRAF exon 9 within a predicted splicing branch point. This intronic mutation was identified in a single cell line but has not been examined in vivo. Herein we demonstrate that in three melanomas biopsied from patients with acquired resistance to BRAF inhibitors, alternate BRAF exon 4-8 splicing is not associated with this intronic branch point mutation...
2017: Biomarker Research
https://www.readbyqxmd.com/read/28494469/mutation-status-among-patients-with-sinonasal-mucosal-melanoma-and-its-impact-on-survival
#9
Moran Amit, Samantha Tam, Ahmed S Abdelmeguid, Dianna B Roberts, Yoko Takahashi, Shaan M Raza, Shirley Y Su, Michael E Kupferman, Franco DeMonte, Ehab Y Hanna
BACKGROUND: Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas and lacks well-characterised molecular markers. Our aim was to determine the frequencies of common mutations and examine their utility as molecular markers in a large series of primary SNMMs. METHODS: SNMM patients seen at our institution from August 1991 through July 2016 were identified. Genomic DNA was extracted from 66 formalin-fixed paraffin-embedded tumours and screened for mutations by direct sequencing...
May 11, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28487464/targeting-braf-mutant-non-small-cell-lung-cancer-from-molecular-profiling-to-rationally-designed-therapy
#10
Christina S Baik, Nathaniel J Myall, Heather A Wakelee
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations...
May 9, 2017: Oncologist
https://www.readbyqxmd.com/read/28480077/combined-dabrafenib-and-trametinib-treatment-in-a-case-of-chemotherapy-refractory-extrahepatic-braf-v600e-mutant-cholangiocarcinoma-dramatic-clinical-and-radiological-response-with-a-confusing-synchronic-new-liver-lesion
#11
Judit Kocsis, Anita Árokszállási, Csilla András, Ingrid Balogh, Edit Béres, Júlia Déri, István Peták, Levente Jánváry, Zsolt Horváth
Since the prognosis of advanced cholangiocarcinoma (CCA) remains poor with traditional chemotherapy, attention has shifted to molecularly targeted agents. Results of available clinical studies reveal little or no benefit of using targeted agents in advanced CCA. Limitations of these trials could be the lack of comprehensive molecular and genetic characterization of CCA samples in order to identify potential drug targets. Here we report a case of a 59-year-old female with chemotherapy-refractor, metastatic extrahepatic cholangiocarcinoma (EHCCA)...
April 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28474232/ets-targeted-therapy-can-it-substitute-for-mek-inhibitors
#12
REVIEW
Osamu Tetsu, Frank McCormick
BACKGROUND: The RAS/MAPK pathway has been intensively studied in cancer. Constitutive activation of ERK1 and ERK2 is frequently found in cancer cells from a variety of tissues. In clinical practice and clinical trials, small molecules targeting receptor tyrosine kinases or components in the MAPK cascade are used for treatment. MEK1 and MEK2 are ideal targets because these enzymes are physiologically important and have narrow substrate specificities and distinctive structural characteristics...
December 2017: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/28473531/oncogenic-ras-regulates-long-non-coding-rna-orilnc1-in-human-cancer
#13
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/28471834/hemophagocytic-lymphohistiocytosis-in-patients-with-metastatic-malignant-melanoma
#14
Sarah Stabler, Coralie Becquart, Florent Dumezy, Louis Terriou, Laurent Mortier
Hemophagocytic lymphohistiocytosis (HLH) is an autoinflammatory disease that classically occurs because of infections, autoinflammatory, or autoimmune diseases, hematologic cancers, and rarely because of solid tumor. We report a rare case of HLH attributed to metastatic malignant melanoma treated without corticosteroid and with a nonfatal outcome thanks to specific therapies: etoposide for HLH and a selective inhibitor of mutated forms of BRAF kinase associated with a MEK inhibitor for melanoma.
May 3, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28463413/a-systematic-review-and-network-meta-analysis-of-immunotherapy-and-targeted-therapy-for-advanced-melanoma
#15
Joao Paulo da Silveira Nogueira Lima, Mina Georgieva, Benjamin Haaland, Gilberto de Lima Lopes
Immune and BRAF-targeted therapies have changed the therapeutic scenario of advanced melanoma, turning the clinical decision-making a challenging task. This Bayesian network meta-analysis assesses the role of immunotherapies and targeted therapies for advanced melanoma. We retrieved randomized controlled trials testing immune, BRAF- or MEK-targeted therapies for advanced melanoma from electronic databases. A Bayesian network model compared therapies using hazard ratio (HR) for overall survival (OS), progression-free survival (PFS), and odds ratio (OR) for response rate (RR), along with 95% credible intervals (95% CrI), and probabilities of drugs outperforming others...
May 1, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28459468/oncogenic-kras-associated-gene-signature-defines-co-targeting-of-cdk4-6-and-mek-as-a-viable-therapeutic-strategy-in-colorectal-cancer
#16
M Pek, S M J M Yatim, Y Chen, J Li, M Gong, X Jiang, F Zhang, J Zheng, X Wu, Q Yu
Therapeutic strategies against KRAS mutant colorectal cancers are developed using cell line models, which do not accurately represent the transcriptome driven by oncogenic KRAS in tumors. We sought to identify a KRAS-associated gene signature from colorectal tumors to develop a precise treatment strategy. Integrative analysis of quantitative KRAS mutation detection and matched gene expression profiling in 55 CRC bulk tumors was carried out to define a gene signature enriched in CRC tumors with high KRAS mutation...
May 1, 2017: Oncogene
https://www.readbyqxmd.com/read/28455392/biomarker-accessible-and-chemically-addressable-mechanistic-subtypes-of-braf-melanoma
#17
Banu Eskiocak, Elizabeth McMillan, Saurabh Mendiratta, Rahul Kollipara, Hailei Zhang, Caroline Humphries, Changguang Wang, Jose Garcia-Rodriguez, Ming Ding, Aubhishek Zaman, Tracy Rosales, Ugur Eskiocak, Michael P Smith, Jessica Sudderth, Kakajan Komurov, Ralph J DeBerardinis, Claudia Wellbrock, Michael A Davies, Jennifer A Wargo, Yonghao Yu, Jef K De Brabander, Noelle S Williams, Lynda Chin, Helen Rizos, Georgina V Long, Ralf Kittler, Michael White
Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathological activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathological ERK1/2 signaling. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities...
April 28, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28450382/an-adaptive-signaling-network-in-melanoma-inflammatory-niches-confers-tolerance-to-mapk-signaling-inhibition
#18
Helen L Young, Emily J Rowling, Mattia Bugatti, Emanuele Giurisato, Nadia Luheshi, Imanol Arozarena, Juan-Carlos Acosta, Jivko Kamarashev, Dennie T Frederick, Zachary A Cooper, Alexandre Reuben, Jesus Gil, Keith T Flaherty, Jennifer A Wargo, William Vermi, Michael P Smith, Claudia Wellbrock, Adam Hurlstone
Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands...
April 27, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28435391/programmed-cell-death-1-checkpoint-inhibitors-in-the-treatment-of-patients-with-advanced-melanoma
#19
REVIEW
Jacek Mackiewicz, Andrzej Mackiewicz
The treatment landscape of advanced melanoma has changed significantly following the discovery and marketing authorisation of immune checkpoints inhibitors. Ipilimumab (anti-CTLA-4) was the first one to be approved, and it. demonstrated long-term survival in about 20% of patients. Subsequently, anti-programmed cell death-1 (a-PD-1) antibodies (pembrolizuamb, nivolumab), inhibitors of PD-1/programmed cell death-1 ligand (PD1-L) synapse, showed higher clinical efficacy with lower toxicity comparing to ipilimumab...
2017: Contemporary Oncology Współczesna Onkologia
https://www.readbyqxmd.com/read/28425764/braf-v600e-mutant-papillary-craniopharyngioma-dramatically-responds-to-combination-braf-and-mek-inhibitors
#20
Ashley Roque, Yazmin Odia
We present a patient with BRAF-V600E mutant papillary craniopharyngioma successfully treated with combination BRAF (dabrafenib 150 mg twice daily) and MEK (trametinib 2 mg daily) inhibitors after her unresectable tumor proved refractory to radiation. Serial brain MRIs and PET revealed marked tumor reduction with gradual neurological improvement and permanent panhypopituitarism.
April 2017: CNS Oncology
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