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Oncogenic mutations

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https://www.readbyqxmd.com/read/29930381/the-dimer-dependent-catalytic-activity-of-raf-family-kinases-is-revealed-through-characterizing-their-oncogenic-mutants
#1
Jimin Yuan, Wan Hwa Ng, Paula Y P Lam, Yu Wang, Hongping Xia, Jiajun Yap, Shou Ping Guan, Ann S G Lee, Mei Wang, Manuela Baccarini, Jiancheng Hu
Although extensively studied for three decades, the molecular mechanisms that regulate the RAF/MEK/ERK kinase cascade remain ambiguous. Recent studies identified the dimerization of RAF as a key event in the activation of this cascade. Here, we show that in-frame deletions in the β3-αC loop activate ARAF as well as BRAF and other oncogenic kinases by enforcing homodimerization. By characterizing these RAF mutants, we find that ARAF has less allosteric and catalytic activity than the other two RAF isoforms, which arises from its non-canonical APE motif...
June 21, 2018: Oncogene
https://www.readbyqxmd.com/read/29930300/the-ribosomal-rpl10-r98s-mutation-drives-ires-dependent-bcl-2-translation-in-t-all
#2
Kim R Kampen, Sergey O Sulima, Benno Verbelen, Tiziana Girardi, Stijn Vereecke, Gianmarco Rinaldi, Jelle Verbeeck, Joyce Op de Beeck, Anne Uyttebroeck, Jules P P Meijerink, Anthony V Moorman, Christine J Harrison, Pieter Spincemaille, Jan Cools, David Cassiman, Sarah-Maria Fendt, Pieter Vermeersch, Kim De Keersmaecker
The R98S mutation in ribosomal protein L10 (RPL10 R98S) affects 8% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases, and was previously described to impair cellular proliferation. The current study reveals that RPL10 R98S cells accumulate reactive oxygen species which promotes mitochondrial dysfunction and reduced ATP levels, causing the proliferation defect. RPL10 R98S mutant leukemia cells can survive high oxidative stress levels via a specific increase of IRES-mediated translation of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2), mediating BCL-2 protein overexpression...
June 21, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29928447/cancer-panel-analysis-of-circulating-tumor-cells-in-patients-with-breast-cancer
#3
Cham Han Lee, Soo Jeong Lee, Sung Ho Choi, Sei Hyun Ahn, Byung Ho Son, Jong Won Lee, Jong Han Yu, Nak-Jung Kwon, Woo Chung Lee, Kap-Seok Yang, Dong Hyoung Lee, Du Yeol Han, Mi So Choi, Pyeong-Soo Park, Hyun Kyung Lee, Myoung Shin Kim, Jinseon Lee, Byung Hee Jeon
Liquid biopsy using circulating tumor cells (CTCs) is a noninvasive and repeatable procedure, and is therefore useful for molecular assays. However, the rarity of CTCs remains a challenge. To overcome this issue, our group developed a novel technology for the isolation of CTCs on the basis of cell size difference. The present study isolated CTCs from patients with breast cancer using this method, and then used these cells for cancer gene panel analysis. Blood samples from eight patients with breast cancer were collected, and CTCs were enriched using size-based filtration...
July 2018: Oncology Letters
https://www.readbyqxmd.com/read/29925955/a-multiprotein-supercomplex-controlling-oncogenic-signalling-in-lymphoma
#4
James D Phelan, Ryan M Young, Daniel E Webster, Sandrine Roulland, George W Wright, Monica Kasbekar, Arthur L Shaffer, Michele Ceribelli, James Q Wang, Roland Schmitz, Masao Nakagawa, Emmanuel Bachy, Da Wei Huang, Yanlong Ji, Lu Chen, Yandan Yang, Hong Zhao, Xin Yu, Weihong Xu, Maryknoll M Palisoc, Racquel R Valadez, Theresa Davies-Hill, Wyndham H Wilson, Wing C Chan, Elaine S Jaffe, Randy D Gascoyne, Elias Campo, Andreas Rosenwald, German Ott, Jan Delabie, Lisa M Rimsza, Fausto J Rodriguez, Fayez Estephan, Matthias Holdhoff, Michael J Kruhlak, Stephen M Hewitt, Craig J Thomas, Stefania Pittaluga, Thomas Oellerich, Louis M Staudt
B cell receptor (BCR) signaling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1 . Gene expression profiling identified two major DLBCL subtypes, known as germinal center (GC) B cell-like (GCB) and activated B cell-like (ABC)2,3 , with inferior outcomes following immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase cascade of SYK, BTK and PKCβ to promote the assembly of the CARD11-BCL10-MALT1 (CBM) adapter complex that recruits and activates IκB kinase (IKK)4-6 ...
June 20, 2018: Nature
https://www.readbyqxmd.com/read/29925636/the-erbb-network-facilitates-kras-driven-lung-tumorigenesis
#5
Björn Kruspig, Tiziana Monteverde, Sarah Neidler, Andreas Hock, Emma Kerr, Colin Nixon, William Clark, Ann Hedley, Sarah Laing, Seth B Coffelt, John Le Quesne, Craig Dick, Karen Vousden, Carla P Martins, Daniel J Murphy
KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRASG12D -driven lung tumors...
June 20, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29925635/afatinib-restrains-k-ras-driven-lung-tumorigenesis
#6
Herwig P Moll, Klemens Pranz, Monica Musteanu, Beatrice Grabner, Natascha Hruschka, Julian Mohrherr, Petra Aigner, Patricia Stiedl, Luka Brcic, Viktoria Laszlo, Daniel Schramek, Richard Moriggl, Robert Eferl, Judit Moldvay, Katalin Dezso, Pedro P Lopez-Casas, Dagmar Stoiber, Manuel Hidalgo, Josef Penninger, Maria Sibilia, Balázs Győrffy, Mariano Barbacid, Balázs Dome, Helmut Popper, Emilio Casanova
On the basis of clinical trials using first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), it became a doctrine that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( K-RAS ) mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Conversely, we provide evidence that EGFR signaling is engaged in K-RAS-driven lung tumorigenesis in humans and in mice. Specifically, genetic mouse models revealed that deletion of Egfr quenches mutant K-RAS activity and transiently reduces tumor growth...
June 20, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29925295/a-case-report-pharmacology-and-resistance-patterns-of-three-generations-of-alk-inhibitors-in-metastatic-inflammatory-myofibroblastic-sarcoma
#7
Barbara M Parker, John V Parker, Anastasios Lymperopoulos, Vijay Konda
Background Little exists currently in research about the mechanisms of resistance of ALK inhibitors in inflammatory myofibroblastic sarcoma. It is known, however, that ALK gene rearrangements are common in inflammatory myofibroblastic tumors, similar to non-small cell lung cancer. In roughly 50% of inflammatory myofibroblastic tumors, gene rearrangement has been found to occur on chromosome 2 at band 2p23. In non-small cell lung cancer, it has been shown that about a third of patients who progress on the first generation ALK inhibitor, crizotinib develops mutations in the ALK kinase domain...
January 1, 2018: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29921696/ddx3-activates-cbc-eif3-mediated-translation-of-uorf-containing-oncogenic-mrnas-to-promote-metastasis-in-hnscc
#8
Hung-Hsi Chen, Hsin-I Yu, Muh-Hwa Yang, Woan-Yuh Tarn
Mutated or dysregulated DDX3 participates in the progression and metastasis of cancer via its multiple roles in regulating gene expression and cellular signaling. Here we show that the high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis and demonstrate that DDX3 is essential for the proliferation, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells. Microarray analyses revealed that DDX3 is required for the expression of a set of pro-metastatic genes including ATF4-modulated genes in an aggressive OSCC cell line...
June 19, 2018: Cancer Research
https://www.readbyqxmd.com/read/29921582/rpp29-regulates-histone-h3-3-chromatin-assembly-through-transcriptional-mechanisms
#9
Prashanth Krishna Shastrula, Peder J Lund, Benjamin A Garcia, Susan M Janicki
The histone H3 variant, H3.3, is a highly conserved and dynamic regulator of chromatin organization.  Therefore, fully elucidating its nucleosome incorporation mechanisms is essential to understanding its functions in epigenetic inheritance.  We previously identified the RNase P protein subunit, Rpp29, as a repressor of H3.3 chromatin assembly.  Here, we use a biochemical assay to show that Rpp29 interacts with H3.3 through a sequence element in its own N-terminus, and we identify a novel interaction with histone H2B at an adjacent site...
June 19, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29915849/regulation-of-lipocalin-2-oncogene-and-its-impact-on-gene-polymorphisms-on-breast-cancer-patients-in-jeddah-saudi-arabia
#10
Sabah Linjawi, Zuhoor AlGaithy, Samar Sindi, Norah Hamdi, Ayman Linjawi, Mona Alharbi
OBJECTIVES: To identify the impact of Lipocalin-2 (LCN2) gene polymorphisms on breast cancer patients in western Saudi Arabia. METHODS: It is a case control study in which blood samples of participants from Medical Reference Clinics and King Abdulaziz University Hospital in Jeddah, Saudi Arabia have been taken between 2014 and 2016. This study recruited 128 participants (50% control, 50% patients) and used Tetra-Primer amplification-refractory mutation system-polymerase chain reaction method for the detection of missense SNP (rs11556770)...
June 2018: Saudi Medical Journal
https://www.readbyqxmd.com/read/29912904/parameter-sensitivity-analysis-for-a-stochastic-model-of-mitochondrial-apoptosis-pathway
#11
Xianli Chen, Xiaoguang Li, Wei Zhao, Tiejun Li, Qi Ouyang
Understanding how gene alterations induce oncogenesis plays an important role in cancer research and may be instructive for cancer prevention and treatment. We conducted a parameter sensitivity analysis to the mitochondrial apoptosis model. Both a nonlinear bifurcation analysis of the deterministic dynamics and energy barrier analysis of the corresponding stochastic models were performed. We found that the parameter sensitivity ranking according to the change of the bifurcation-point locations in deterministic models and the change of the barrier heights from a living to death state of the cell in stochastic models are highly correlated...
2018: PloS One
https://www.readbyqxmd.com/read/29910649/rapidly-changing-treatment-algorithms-for-metastatic-nonsquamous-non-small-cell-lung-cancer
#12
REVIEW
B Melosky
Background: The treatment paradigm for metastatic nonsquamous non-small-cell lung cancer (nsclc) continues to change. Algorithms published only 6 months ago are outdated today and are dramatically different from those published a few years ago. New driver mutations continue to be identified, and the development of therapies to inhibit oncogenic addiction is ongoing. Patient survival is improving as treatments become more personalized and effective. Methods: This review looks at the outcomes of recent trials and discusses treatment options for patients with metastatic nsclc of nonsquamous histology...
June 2018: Current Oncology
https://www.readbyqxmd.com/read/29910075/competition-for-space-is-controlled-by-apoptosis-induced-change-of-local-epithelial-topology
#13
Alice Tsuboi, Shizue Ohsawa, Daiki Umetsu, Yukari Sando, Erina Kuranaga, Tatsushi Igaki, Koichi Fujimoto
During the initial stage of tumor progression, oncogenic cells spread despite spatial confinement imposed by surrounding normal tissue. This spread of oncogenic cells (winners) is thought to be governed by selective killing of surrounding normal cells (losers) through a phenomenon called "cell competition" (i.e., supercompetition). Although the mechanisms underlying loser elimination are increasingly apparent, it is not clear how winner cells selectively occupy the space made available following loser apoptosis...
June 11, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29907857/alterations-of-mtor-signaling-impact-metabolic-stress-resistance-in-colorectal-carcinomas-with-braf-and-kras-mutations
#14
Raphaela Fritsche-Guenther, Christin Zasada, Guido Mastrobuoni, Nadine Royla, Roman Rainer, Florian Roßner, Matthias Pietzke, Edda Klipp, Christine Sers, Stefan Kempa
Metabolic reprogramming is as a hallmark of cancer, and several studies have reported that BRAF and KRAS tumors may be accompanied by a deregulation of cellular metabolism. We investigated how BRAFV600E and KRASG12V affect cell metabolism, stress resistance and signaling in colorectal carcinoma cells driven by these mutations. KRASG12V expressing cells are characterized by the induction of glycolysis, accumulation of lactic acid and sensitivity to glycolytic inhibition. Notably mathematical modelling confirmed the critical role of MCT1 designating the survival of KRASG12V cells...
June 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29907296/surface-enhanced-raman-spectroscopy-based-immunosensor-for-ultrasensitive-and-selective-detection-of-wild-type-p53-and-mutant-p53-r175h
#15
Anna Rita Bizzarri, Ilaria Moscetti, Salvatore Cannistraro
p53 is a powerful transcription factor playing a pivotal role in the prevention of cancer development and in maintaining genome integrity. This oncosuppressor is found to be functionally inactivated by mutations in many human tumors. Accordingly, wild type p53 and its oncogenic mutants represent valuable cancer biomarkers for diagnostic and prognostic purposes. We developed a highly sensitive biosensor, based on Surface Enhanced Raman Spectroscopy, for detection of wild type p53 and of p53R175H , which is one of the most frequent tumor-associated mutants of p53...
October 31, 2018: Analytica Chimica Acta
https://www.readbyqxmd.com/read/29906244/de-novo-lipogenesis-represents-a-therapeutic-target-in-mutant-kras-non-small-cell-lung-cancer
#16
Anju Singh, Christian Ruiz, Kavita Bhalla, John A Haley, Qing Kay Li, George Acquaah-Mensah, Emily Montal, Kuladeep R Sudini, Ferdinandos Skoulidis, Ignacio I Wistuba, Vassiliki Papadimitrakopoulou, John V Heymach, Laszlo G Boros, Edward Gabrielson, Julian Carretero, Kwok-Kin Wong, John D Haley, Shyam Biswal, Geoffrey D Girnun
Oncogenic Kras mutations are one of the most common alterations in non-small cell lung cancer and are associated with poor response to treatment and reduced survival. Driver oncogenes, such as Kras are now appreciated for their ability to promote tumor growth via up-regulation of anabolic pathways. Therefore, we wanted to identify metabolic vulnerabilities in Kras-mutant lung cancer. Using the Kras LSL-G12D lung cancer model, we show that mutant Kras drives a lipogenic gene-expression program. Stable-isotope analysis reveals that mutant Kras promotes de novo fatty acid synthesis in vitro and in vivo...
June 15, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29904729/proteome-wide-analysis-of-protein-abundance-and-turnover-remodelling-during-oncogenic-transformation-of-human-breast-epithelial-cells
#17
Tony Ly, Aki Endo, Alejandro Brenes, Marek Gierlinski, Vackar Afzal, Andrea Pawellek, Angus I Lamond
Background : Viral oncogenes and mutated proto-oncogenes are potent drivers of cancer malignancy. Downstream of the oncogenic trigger are alterations in protein properties that give rise to cellular transformation and the acquisition of malignant cellular phenotypes. Developments in mass spectrometry enable large-scale, multidimensional characterisation of proteomes. Such techniques could provide an unprecedented, unbiased view of how oncogene activation remodels a human cell proteome. Methods : Using quantitative MS-based proteomics and cellular assays, we analysed how transformation induced by activating v-Src kinase remodels the proteome and cellular phenotypes of breast epithelial (MCF10A) cells...
2018: Wellcome Open Research
https://www.readbyqxmd.com/read/29903880/real-time-genomic-characterization-of-advanced-pancreatic-cancer-to-enable-precision-medicine
#18
Andrew J Aguirre, Jonathan A Nowak, Nicholas D Camarda, Richard A Moffitt, Arezou A Ghazani, Mehlika Hazar-Rethinam, Srivatsan Raghavan, Jaegil Kim, Lauren K Brais, Dorisanne Ragon, Marisa W Welch, Emma Reilly, Devin McCabe, Lori Marini, Kristin Anderka, Karla Helvie, Nelly Oliver, Ana Babic, Annacarolina Da Silva, Brandon Nadres, Emily E Van Seventer, Heather A Shahzade, Joseph P St Pierre, Kelly P Burke, Thomas E Clancy, James M Cleary, Leona A Doyle, Kunal Jajoo, Nadine J McCleary, Jeffrey A Meyerhardt, Janet E Murphy, Kimmie Ng, Anuj K Patel, Kimberly Perez, Michael H Rosenthal, Douglas A Rubinson, Marvin Ryou, Geoffrey I Shapiro, Ewa Sicinska, Stuart G Silverman, Rebecca J Nagy, Richard B Lanman, Deborah Knoerzer, Dean J Welsch, Matthew B Yurgelun, Charles S Fuchs, Levi A Garraway, Gad Getz, Jason L Hornick, Bruce E Johnson, Matthew H Kulke, Robert J Mayer, Jeffrey W Miller, Paul B Shyn, David A Tuveson, Nikhil Wagle, Jen Jen Yeh, William C Hahn, Ryan B Corcoran, Scott L Carter, Brian M Wolpin
Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole exome sequencing and RNA-sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data...
June 14, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29903769/yap-tyrosine-phosphorylation-and-nuclear-localization-in-cholangiocarcinoma-cells-is-regulated-by-lck-and-independent-of-lats-activity
#19
Takaaki Sugihara, Nathan W Werneburg, Matthew C Hernandez, Lin Yang, Ayano Kabashima, Petra Hirsova, Lavanya Yohanathan, Carlos Sosa, Mark Joseph Truty, George Vasmatzis, Gregory J Gores, Rory L Smoot
The hippo pathway effector, Yes-associated protein (YAP) is a transcriptional co-activator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2 - LATS1/2) culminating in phosphorylation of YAP at Serine 127 (S127) and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models...
June 14, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29902613/dasatinib-sensitises-kras-mutant-cancer-cells-to-mitogen-activated-protein-kinase-kinase-inhibitor-via-inhibition-of-taz-activity
#20
Guanhua Rao, In-Kyu Kim, Fabio Conforti, Jing Liu, Yu-Wen Zhang, Giuseppe Giaccone
PURPOSE: Oncogenic KRAS mutations occur frequently in solid tumours, but no clinically applicable targeted strategy is yet available for treating human cancers with mutant KRAS. Here we aimed to identify a strategy for the treatment of KRAS-driven cancers. EXPERIMENTAL DESIGN: Cell viability and colony forming assays were used to assess the in vitro effect of dasatinib and trametinib as single agents or in combination. Western blot was used to analyse the phosphorylated protein and total protein levels...
June 11, 2018: European Journal of Cancer
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