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https://www.readbyqxmd.com/read/29917164/long-non-coding-rna-bancr-regulates-cancer-stem-cell-markers-in-papillary-thyroid-cancer-via-the-raf-mek-erk-signaling-pathway
#1
Yuanyuan Wang, Xiangde Lin, Xinghao Fu, Wei Yan, Fusheng Lin, Penghao Kuang, Yezhe Luo, Ende Lin, Xiaoquan Hong, Guoyang Wu
Thyroid cancer is one of the most common malignant tumors of the endocrine system. Among all thyroid cancers, papillary thyroid carcinoma (PTC) is the most common type. The BRAF-activated non-coding RNA (BANCR) is a 693-bp nucleotide transcript which was first identified in melanoma. However, the role of BANCR in the development of thyroid cancer remains unclear. Therefore, the present study investigated the potential involvement of BANCR in the development of thyroid cancer in vitro using patient tissue samples and a panel of thyroid cancer cell lines, and in vivo using a xenograft mouse model...
June 18, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29905375/sox2-mediated-upregulation-of-cd24-promotes-adaptive-resistance-towards-targeted-therapy-in-melanoma
#2
Laura Hüser, Sachindra, Karol Granados, Aniello Federico, Lionel Larribère, Daniel Novak, Viktor Umansky, Peter Altevogt, Jochen Utikal
Melanoma is often characterized by a constitutively active RAS-RAF-MEK-ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment. A similar upregulation was seen in targeted therapy-resistant, melanoma-derived induced pluripotent cancer cells (iPCCs)...
June 15, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29880840/rip1-protects-melanoma-cells-from-apoptosis-induced-by-braf-mek-inhibitors
#3
Fu Xi Lei, Lei Jin, Xiao Ying Liu, Fritz Lai, Xu Guang Yan, Margaret Farrelly, Su Tang Guo, Xin Han Zhao, Xu Dong Zhang
Many recent studies have uncovered the necessary role for the receptor-interacting protein kinase 1 (RIP1) in regulating apoptosis and necrosis that cells undergo in response to various cellular stresses. However, the functional significance of RIP1 in promoting cancer cells survival remains poorly understood. Here, we report that RIP1 was upregulated and contributed to both intrinsic and acquired resistance of melanoma cells to BRAF/MEK inhibitors through activation of NF-κB. Strikingly, Snail1-mediated suppression of CYLD played a crucial role in promoting RIP1 expression upon ERK activation, particularly, in melanoma cells with acquired resistance to BRAF inhibitors...
June 7, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29808006/shp2-is-required-for-growth-of-kras-mutant-non-small-cell-lung-cancer-in-vivo
#4
Sara Mainardi, Antonio Mulero-Sánchez, Anirudh Prahallad, Giovanni Germano, Astrid Bosma, Paul Krimpenfort, Cor Lieftink, Jeffrey D Steinberg, Niels de Wit, Samuel Gonçalves-Ribeiro, Ernest Nadal, Alberto Bardelli, Alberto Villanueva, Rene Bernards
RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3 . Inhibition of the RAS oncoproteins has proven difficult 4 , and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms 8 . It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10 ...
May 28, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29805692/mps1-is-associated-with-the-braf-v600e-mutation-but-does-not-rely-on-the-classic-ras-raf-mek-erk-signaling-pathway-in-thyroid-carcinoma
#5
Yike Li, Yanyan Zhang, Shuaishuai Xiao, Pengzhou Kong, Caixia Cheng, Ruyi Shi, Fang Wang, Ling Zhang, Juan Wang, Zhiwu Jia, Shuai Wu, Yun Liu, Jiansheng Guo, Xiaolong Cheng, Yongping Cui, Jing Liu
In previous studies, the B-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E mutation has been identified in multiple malignant tumors. BRAFV600E has been revealed to contribute to tumorigenesis by the activation of phospho-mitogen-activated protein kinases (MAPKs) and their downstream Monopolar spindle 1 (Mps1), leading to chromosome euploidy and tumor development. In the present study, the presence of phospho-MAPK and Mps1 in 161 thyroid carcinoma cases with complete clinical parameters was analyzed by immunohistochemistry, and the BRAF mutation was detected by polymerase chain reaction-direct sequencing...
June 2018: Oncology Letters
https://www.readbyqxmd.com/read/29777202/aberrant-modulation-of-ribosomal-protein-s6-phosphorylation-confers-acquired-resistance-to-mapk-pathway-inhibitors-in-braf-mutant-melanoma
#6
Ming-Zhao Gao, Hong-Bin Wang, Xiang-Ling Chen, Wen-Ting Cao, Li Fu, Yun Li, Hai-Tian Quan, Cheng-Ying Xie, Li-Guang Lou
BRAF and MEK inhibitors have shown remarkable clinical efficacy in BRAF-mutant melanoma; however, most patients develop resistance, which limits the clinical benefit of these agents. In this study, we found that the human melanoma cell clones, A375-DR and A375-TR, with acquired resistance to BRAF inhibitor dabrafenib and MEK inhibitor trametinib, were cross resistant to other MAPK pathway inhibitors. In these resistant cells, phosphorylation of ribosomal protein S6 (rpS6) but not phosphorylation of ERK or p90 ribosomal S6 kinase (RSK) were unable to be inhibited by MAPK pathway inhibitors...
May 18, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29768711/clinical-resistance-associated-with-a-novel-map2k1-mutation-in-a-patient-with-langerhans-cell-histiocytosis
#7
David O Azorsa, David W Lee, Daniel H Wai, Ranjan Bista, Apurvi R Patel, Eiman Aleem, Michael M Henry, Robert J Arceci
Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p...
May 16, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29766299/molecularly-defined-diffuse-leptomeningeal-glioneuronal-tumor-dlgnt-comprises-two-subgroups-with-distinct-clinical-and-genetic-features
#8
Maximilian Y Deng, Martin Sill, Jason Chiang, Jens Schittenhelm, Martin Ebinger, Martin U Schuhmann, Camelia-Maria Monoranu, Till Milde, Andrea Wittmann, Christian Hartmann, Clemens Sommer, Werner Paulus, Jutta Gärtner, Wolfgang Brück, Thomas Rüdiger, Alfred Leipold, Zane Jaunmuktane, Sebastian Brandner, Felice Giangaspero, Paolo Nozza, Jaume Mora, Andres Morales la Madrid, Ofelia Cruz Martinez, Jordan R Hansford, Torsten Pietsch, Anna Tietze, Pablo Hernáiz-Driever, Iris Stoler, David Capper, Andrey Korshunov, David W Ellison, Andreas von Deimling, Stefan M Pfister, Felix Sahm, David T W Jones
Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs...
May 15, 2018: Acta Neuropathologica
https://www.readbyqxmd.com/read/29760222/erk-mutations-and-amplification-confer-resistance-to-erk-inhibitor-therapy
#9
Bijay S Jaiswal, Steffen Durinck, Eric Stawiski, Jianping Yin, Weiru Wang, Eva Lin, John G Moffat, Scott Martin, Zora Modrusan, Somasekar Seshagiri
PURPOSE: MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF and/or RAS mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance...
May 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29748372/traf1-is-critical-for-regulating-the-braf-mek-erk-pathway-in-non-small-cell-lung-carcinogenesis
#10
Qiushi Wang, Ge Gao, Tianshun Zhang, Ke Yao, Hanyong Chen, Mi Hee Park, Hiroyuki Yamamoto, Keke Wang, Weiya Ma, Margarita Malakhova, Ann M Bode, Zigang Dong
Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) is a unique TRAF protein that can interact directly or indirectly with multiple TNFR family members, regulatory proteins, kinases, and adaptors that contribute to its diverse functions in specific tissues. However, the role of TRAF1 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we report that TRAF1 is overexpressed in human lung cancer cells and tissues. TRAF1 expression level inversely correlated with patient survival probability...
May 10, 2018: Cancer Research
https://www.readbyqxmd.com/read/29737325/the-mek1-2-inhibitor-azd6244-sensitizes-braf-mutant-thyroid-cancer-to-vemurafenib
#11
Hao Song, Jinna Zhang, Liang Ning, Honglai Zhang, Dong Chen, Xuelong Jiao, Kejun Zhang
BACKGROUND [i]BRAF[/i]V600E mutation occurs in approximately 45% of papillary thyroid cancer (PTC) cases, and 25% of anaplastic thyroid cancer (ATC) cases. Vemurafenib/PLX4032, a selective BRAF inhibitor, suppresses extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase 1/2 (MEK/ERK1/2) signaling and shows beneficial effects in patients with metastatic melanoma harboring the [i]BRAFV600E[/i] mutation. However, the response to vemurafenib is limited in BRAF-mutant thyroid cancer. The present study evaluated the effect of vemurafenib in combination with the selective MEK1/2 inhibitor AZD6244 on cell survival and explored the mechanism underlying the combined effect of vemurafenib and AZD6244 on thyroid cancer cells harboring BRAFV600E...
May 8, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29729495/braf-in-non-small-cell-lung-cancer-nsclc-pickaxing-another-brick-in-the-wall
#12
REVIEW
Alessandro Leonetti, Francesco Facchinetti, Giulio Rossi, Roberta Minari, Antonia Conti, Luc Friboulet, Marcello Tiseo, David Planchard
Molecular characterization of non-small cell lung cancer (NSCLC) marked an historical turning point for the treatment of lung tumors harboring kinase alterations suitable for specific targeted drugs inhibition, translating into major clinical improvements. Besides EGFR, ALK and ROS1, BRAF represents a novel therapeutic target for the treatment of advanced NSCLC. BRAF mutations, found in 1.5-3.5% of NSCLC, are responsible of the constitutive activation of mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway...
April 24, 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29717260/a-modified-gene-trap-approach-for-improved-high-throughput-cancer-drug-discovery
#13
Shelli M Morris, Andrew J Mhyre, Savanna S Carmack, Carrie H Myers, Connor Burns, Wenjuan Ye, Marc Ferrer, James M Olson, Richard A Klinghoffer
While advances in laboratory automation has dramatically increased throughout of compound screening efforts, development of robust cell-based assays in relevant disease models remain resource-intensive and time-consuming, presenting a bottleneck to drug discovery campaigns. To address this issue, we present a modified gene trap approach to efficiently generate pathway-specific reporters that result in a robust "on" signal when the pathway of interest is inhibited. In this proof-of-concept study, we used vemurafenib and trametinib to identify traps that specifically detect inhibition of the mitogen-activated protein kinase (MAPK) pathway in a model of BRAFV600E driven human malignant melanoma...
May 2, 2018: Oncogene
https://www.readbyqxmd.com/read/29708446/braf-mutant-colorectal-cancer-a-different-breed-evolving
#14
Eleonora Lai, Andrea Pretta, Valentino Impera, Stefano Mariani, Riccardo Giampieri, Laura Casula, Valeria Pusceddu, Pierpaolo Coni, Daniela Fanni, Marco Puzzoni, Laura Demurtas, Pina Ziranu, Gavino Faa, Mario Scartozzi
BRAF mutant colorectal cancer (BRAF MT CRC) is a unique category of colorectal tumour with peculiar molecular, pathological and clinical features and poor prognosis; despite recent research, BRAF mutation predictive value and standard treatment of BRAF MT CRC still have to be defined. In this review, we focused on this challenging topic. Areas covered: The potential use of BRAF mutational status among recent additional prognostic and predictive indicators and current treatment strategy in use in these patients is discussed...
June 2018: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/29684526/targeted-gene-silencing-of-braf-to-interrupt-braf-mek-erk-pathway-synergized-photothermal-therapeutics-for-melanoma-using-a-novel-fa-gnr-sibraf-nanosystem
#15
Yujuan Zhang, Xuelin Zhan, Shanshan Peng, Ying Cai, Yu Shrike Zhang, Yanling Liu, Zhigang Wang, Yanrong Yu, Yifan Wang, Qiaofa Shi, Xiaoping Zeng, Keng Yuan, Nanjin Zhou, Rakesh Joshi, Meng Zhang, Zhuxu Zhang, Weiping Min
Melanoma is significantly associated with mutant BRAF gene, a suitable target for siRNA-based anti-melanoma therapy. However, a tumor-specific delivery system is a major hurdle for clinical applications. Here, we developed a novel nano-carrier, FA-GNR-siBRAF for safe topical application, which consists of folic acid (FA) as the tumor-targeting moiety, golden nanorods (GNR) providing photothermal capability to kill tumor cells under laser irradiation, and siRNA specifically silencing BRAF (siBRAF). The in vitro and in vivo results revealed that FA-GNR-siBRAF displayed high transfection rates, and subsequently induced remarkable gene knockdown of BRAF, resulting in suppression of melanoma growth due to the interruption of the MEK/ERK pathway...
April 21, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29682188/imaging-markers-of-response-to-combined-braf-and-mek-inhibition-in-braf-mutated-vemurafenib-sensitive-and-resistant-melanomas
#16
Stefania Acciardo, Lionel Mignion, Nicolas Joudiou, Caroline Bouzin, Jean-François Baurain, Bernard Gallez, Bénédicte F Jordan
A majority of patients with a V600x melanoma respond quickly to BRAF/MEK inhibition (BRAFi/MEKi) and have an obvious clinical benefit. Nearly all the patients after this initial phase will develop resistance. Therefore, non-invasive early markers of response/non-response are needed in order to identify those patients who, due to intrinsic or acquired resistance, do not respond to treatment and would be eligible for alternative treatments. The aim of this study was to investigate the value of magnetic resonance spectroscopy (1 H-MRS) of choline and diffusion-weighted magnetic resonance imaging (DW-MRI) as early markers of response to BRAF inhibition (BRAFi) with vemurafenib alone or in combination with MEK inhibition (MEKi) with trametinib, in BRAFi-sensitive and BRAFi-resistant melanoma xenografts...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29662630/type-ii-raf-inhibitor-causes-superior-erk-pathway-suppression-compared-to-type-i-raf-inhibitor-in-cells-expressing-different-braf-mutant-types-recurrently-found-in-lung-cancer
#17
Amir Noeparast, Philippe Giron, Sylvia De Brakeleer, Carolien Eggermont, Ulrike De Ridder, Erik Teugels, Jacques De Grève
A large fraction of somatic driver BRAF mutations in lung cancer are non-V600 and impaired-kinase. Non-V600 BRAF mutations predict sensitivity to combination of a type I RAF inhibitor, Dabrafenib, and a MEK inhibitor, Trametinib. Singly, Dabrafenib only weakly suppresses mutant BRAF-induced ERK signaling and can induce ERK paradoxical activation in CRAF-overexpressing cells. The present study compared the effects of Dabrafenib and a type II RAF inhibitor, AZ628, on ERK activity in HEK293T cells expressing several tumor-derived BRAF mutants, and in a non-V600 and impaired-kinase BRAF-mutant lung cancer cell line (H1666)...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29610287/advances-on-the-braf-front-in-colorectal-cancer
#18
Filip Janku
<b/> Colorectal cancer with BRAF V600E mutation can be effectively treated with combination approaches involving inhibition of BRAF, MEK, and EGFR proteins. However, activation of the MAPK pathway, often due to emergence of previously undetected molecular alterations, ultimately leads to adaptive therapeutic resistance. Novel combination strategies combining inhibition of BRAF, ERK, and EGFR can be used to prevent MAPK pathway-driven resistance and warrant further investigation. Cancer Discov; 8(4); 389-91...
April 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29552216/lncrna-bancr-promotes-emt-in-ptc-via-the-raf-mek-erk-signaling-pathway
#19
Yuanyuan Wang, Jiaojiao Gu, Xiangde Lin, Wei Yan, Wenchao Yang, Guoyang Wu
Thyroid cancer is one of the most common types of cancer in the endocrine system. Among all types of thyroid cancer, papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Long non-coding RNA (lncRNA) BRAF-activated non-protein-coding RNA (BANCR) is a 688-bp-long nucleotide transcript, which was first identified in melanoma. The function of BANCR in thyroid cancer remains unclear. The aim of the present study was to investigate whether BANCR is involved in the development of thyroid cancer...
April 2018: Oncology Letters
https://www.readbyqxmd.com/read/29540830/classifying-braf-alterations-in-cancer-new-rational-therapeutic-strategies-for-actionable-mutations
#20
REVIEW
Matthew Dankner, April A N Rose, Shivshankari Rajkumar, Peter M Siegel, Ian R Watson
The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants...
March 15, 2018: Oncogene
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