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https://www.readbyqxmd.com/read/29353494/primary-liver-cancers-part-2-progression-pathways-and-carcinogenesis
#1
Kun Jiang, Barbara A Centeno
Hepatocellular carcinoma (HCC) and primary intrahepatic cholangiocarcinoma (ICC) have been increasing in incidence worldwide and are leading causes of cancer death. Studies of the molecular alterations leading to these carcinomas provide insights into the key mechanisms involved. A literature review was conducted to identify articles with information relevant to current understanding of the etiologies and molecular pathogenesis of HCC and ICC. Chronic inflammatory diseases are the key etiological risk factors for both HCC and ICC, although other diseases play a role, and for many ICCs, an underlying risk factor is not identified...
January 2018: Cancer Control: Journal of the Moffitt Cancer Center
https://www.readbyqxmd.com/read/29343524/antitumor-properties-of-raf709-a-highly-selective-and-potent-inhibitor-of-raf-kinase-dimers-in-tumors-driven-by-mutant-ras-or-braf
#2
Wenlin Shao, Yuji Mishina, Yun Feng, Giordano Caponigro, Vesselina G Cooke, Stacy Rivera, Yingyun Wang, Fang Shen, Joshua M Korn, Lesley Mathews Griner, Gisele Nishiguchi, Alice Rico, John Tellew, Jacob Haling, Robert Aversa, Valery R Polyakov, Richard Zang, Mohammad Hekmat-Nejad, Payman Amiri, Mallika Singh, Nicholas Keen, Michael P Dillon, Emma Lees, Savithri Ramurthy, William R Sellers, Darrin D Stuart
Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF...
January 17, 2018: Cancer Research
https://www.readbyqxmd.com/read/29333594/ras-testing-for-colorectal-cancer-patients-is-reliable-in-european-laboratories-that-pass-external-quality-assessment
#3
V Tack, M J L Ligtenberg, A G Siebers, P D M Rombout, P D Dabir, R D A Weren, J H J M van Krieken, E M C Dequeker
Wild-type status of KRAS and the NRAS gene (exon 2, 3, and 4) in the tumor should be determined before treatment of metastatic colorectal cancer (mCRC) patients with EGFR-targeting agents. There is a large variation in test methods to determine RAS status, and more sensitive detection methods were recently introduced. Data from quality assessment programs indicate substantial error rates. This study assessed the completeness and correctness of RAS testing in European laboratories that successfully passed external quality assessment (EQA)...
January 15, 2018: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29321164/kras-oncoprotein-expression-is-regulated-by-a-self-governing-eif5a-peak1-feed-forward-regulatory-loop
#4
Ken Fujimura, Huawei Wang, Felicia Watson, Richard L Klemke
There remains intense interest in tractable approaches to target or silence the KRAS oncoprotein as a rational therapeutic strategy to attack pancreatic adenocarcinoma (PDAC) and other cancers which overexpress it. Here we provide evidence that accumulation of the KRAS oncoprotein is controlled by a self-regulating feed-forward regulatory loop that utilizes a unique hypusinated isoform of the translation elongation factor eIF5A and the tyrosine kinase PEAK1. Oncogenic activation of KRAS increased eIF5A-PEAK1 translational signaling, which in turn facilitated increased KRAS protein synthesis...
January 10, 2018: Cancer Research
https://www.readbyqxmd.com/read/29320991/an-oncogenic-mutant-of-rheb-rheb-y35n-exhibits-an-altered-interaction-with-braf-resulting-in-cancer-transformation
#5
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/29320425/targeting-pancreatic-cancer-cell-plasticity-the-latest-in-therapeutics
#6
REVIEW
Jacob M Smigiel, Neetha Parameswaran, Mark W Jackson
Mortality remains alarmingly high for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC), with 93% succumbing to the disease within five years. The vast majority of PDAC cases are driven by activating mutations in the proto-oncogene KRAS, which results in constitutive proliferation and survival signaling. As efforts to target RAS and its downstream effectors continue, parallel research aimed at identifying novel targets is also needed in order to improve therapeutic options and efficacy. Recent studies demonstrate that self-renewing cancer stem cells (CSCs) contribute to metastatic dissemination and therapy failure, the causes of mortality from PDAC...
January 10, 2018: Cancers
https://www.readbyqxmd.com/read/29313669/design-of-small-molecules-that-compete-with-nucleotide-binding-to-an-engineered-oncogenic-kras-allele
#7
Yan Zhang, Mare-Helene Larraufie, Leila Musavi, Hemanth Akkiraju, Lewis M Brown, Brent R Stockwell
RAS mutations are found in 30% of all human cancers, with KRAS the most frequently mutated among the three RAS isoforms (KRAS, NRAS, HRAS). However, directly targeting oncogenic KRAS with small molecules in the nucleotide-binding site has been difficult due to the high affinity of KRAS for GDP and GTP. We designed an engineered allele of KRAS, and a covalent inhibitor that competes for GTP and GDP. This ligand-receptor combination demonstrates that the high affinity of GTP/GDP for RAS proteins can be overcome with a covalent inhibitor and a suitably engineered binding site...
January 9, 2018: Biochemistry
https://www.readbyqxmd.com/read/29307569/is-nanoclustering-essential-for-all-oncogenic-kras-pathways-can-it-explain-why-wild-type-kras-can-inhibit-its-oncogenic-variant
#8
REVIEW
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Membrane-anchored oncogenic KRas can dimerize, form nanoclusters, and signal through the MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. Both pathways are needed in KRAS-driven proliferation. Here we ask: Is oncogenic KRas nanoclustering (or dimerization) essential for all KRas signaling pathways? Raf kinase domain dimerization, thus MAPK activation, requires KRas nanoclusters. By contrast, the PI3Kα heterodimer acts as a monomeric unit; thus, does PI3Kα activation and PI3Kα/Akt/mTOR signaling require nanoclustering? Further, calmodulin binds only to oncogenic KRas4B...
January 5, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29301589/linking-foxo3-ncoa3-and-tcf7l2-to-ras-pathway-phenotypes-through-a-genome-wide-forward-genetic-screen-in-human-colorectal-cancer-cells
#9
Snehangshu Kundu, Muhammad Akhtar Ali, Niklas Handin, Narendra Padhan, Jimmy Larsson, Maria Karoutsou, Kenneth Ban, Jacek R Wiśniewski, Per Artursson, Liqun He, Mats Hellström, Tobias Sjöblom
BACKGROUND: The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in ~ 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway. METHODS: To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted...
January 4, 2018: Genome Medicine
https://www.readbyqxmd.com/read/29296886/constitutive-ras-signaling-and-ink4a-arf-inactivation-cooperate-during-the-development-of-b-all-in-mice
#10
Tomasz Sewastianik, Meng Jiang, Kumar Sukhdeo, Sanjay S Patel, Kathryn Roberts, Yue Kang, Ahmad Alduaij, Peter S Dennis, Brian Lawney, Ruiyang Liu, Zeyuan Song, Jessie Xiong, Yunyu Zhang, Madeleine E Lemieux, Geraldine S Pinkus, Jeremy N Rich, David M Weinstock, Charles G Mullighan, Norman E Sharpless, Ruben D Carrasco
Despite recent advances in treatment, human precursor B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging clinical entity. Recent genome-wide studies have uncovered frequent genetic alterations involving RAS pathway mutations and loss of the INK4A/ARF locus, suggesting their important role in the pathogenesis, relapse, and chemotherapy resistance of B-ALL. To better understand the oncogenic mechanisms by which these alterations might promote B-ALL and to develop an in vivo preclinical model of relapsed B-ALL, we engineered mouse strains with induced somatic KrasG12D pathway activation and/or loss of Ink4a/Arf during early stages of B-cell development...
November 28, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296181/correlation-between-mek-signature-and-ras-gene-alteration-in-advanced-gastric-cancer
#11
Soomin Ahn, Roz Brant, Alan Sharpe, Jonathan R Dry, Darren R Hodgson, Elaine Kilgour, Kyung Kim, Seung Tae Kim, Se Hoon Park, Won Ki Kang, Kyoung-Mee Kim, Jeeyun Lee
MEK inhibitor (selumetinib) is a potent, orally active inhibitor of MAPK/ERK pathway. It is important to develop an accurate and robust method indicative of RAS pathway activity to stratify potential patients who can benefit from selumetinib treatment in gastric cancer (GC). First, we surveyed the sensitivity to selumetinib in a panel of 22 GC cell lines and correlated with MEK signature to selumetinib sensitivity. Next, we analyzed MEK signature via nanostring assay in two Asian cohorts using clinical samples (n = 218) and then performed a correlative analysis with MEK signature status and KRAS genotype in GC...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29290764/aminoacylase-3-is-a-new-potential-marker-and-therapeutic-target-in-hepatocellular-carcinoma
#12
Kirill Tsirulnikov, Sergio Duarte, Anamika Ray, Nakul Datta, Ali Zarrinpar, Lin Hwang, Kym Faull, Alexander Pushkin, Ira Kurtz
Ras proteins (HRas, KRas and NRas) are common oncogenes that require membrane association for activation. Previous approaches to block/inhibit Ras membrane association were unsuccessful for cancer treatment in human clinical studies. In the present study we utilized a new approach to decrease Ras membrane association in hepatocellular carcinoma (HCC) cell lines via inhibition of an enzyme aminoacylase 3 (AA3; EC 3.5.1.114). AA3 expression was significantly elevated in the livers of HCC patients and HCC cell lines...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29285234/targeted-next-generation-sequencing-in-chinese-colorectal-cancer-patients-guided-anti-egfr-treatment-and-facilitated-precision-cancer-medicine
#13
Helei Hou, Dong Liu, Chuantao Zhang, Yanxia Jiang, Guifang Lu, Na Zhou, Xiaonan Yang, Xiaoping Zhang, Zhuokun Li, Hongmei Zhu, Zhaoyang Qian, Xiaochun Zhang
Objective: Colorectal cancer (CRC) patients with both RAS and BRAF wild-type tumors determined by non-next generation sequencing (NGS) testing may still not respond due to the presence of additional mutated genes such as PIK3CA or PTEN. In this study, a broad, hybrid capture-based NGS assay was used to identify RAS, BRAF and additional targetable genetic alterations from Chinese CRC tissues. Methods: Fifty-seven cases of CRC were enrolled, and all the patients signed the informed consent...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29279289/erbb2-mutation-a-promising-target-in-non-squamous-cervical-cancer
#14
Libing Xiang, Wei Jiang, Shuang Ye, Tiancong He, Xuan Pei, Jiajia Li, David Wai Chan, Hextan Yuen Sheung Ngan, Fang Li, Pingping Tao, Xuxia Shen, Xiaoyan Zhou, Xiaohua Wu, Gong Yang, Huijuan Yang
OBJECTIVE: ERBB2 mutations have been found in a subset of invasive cervical cancer (ICC). Nevertheless, the prevalence, mutation spectrum, clinicopathological relevance, human papillomavirus (HPV)-genotype association and prognostic significance of ERBB2-mutated ICCs have not been well established. METHODS: In this study, ICC samples (N=1015) were assessed for mutations in ERBB2, KRAS, and PIK3CA by cDNA-based Sanger sequencing. RESULTS: Somatic ERBB2 mutations were detected in 3...
December 23, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/29279013/novel-approaches-to-diagnosis-and-treatment-of-juvenile-myelomonocytic-leukemia
#15
Franco Locatelli, Mattia Algeri, Pietro Merli, Luisa Strocchio
Juvenile myelomonocytic leukemia (JMML) is a clonal hematopoietic disorder of infancy/early childhood, resulting from oncogenic mutations in genes involved in the Ras pathway. As JMML often exhibits an aggressive course, the timing of diagnosis and treatment is critical to outcome. Areas covered: This review summarizes current approaches to diagnosis and treatment of JMML, highlighting most recent insights into genetic and epigenetic mechanisms underlying the disease, and providing an overview of novel potential therapeutic strategies...
January 3, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29275358/wild-type-kirsten-rat-sarcoma-is-a-novel-microrna-622-regulated-therapeutic-target-for-hepatocellular-carcinoma-and-contributes-to-sorafenib-resistance
#16
Peter Dietrich, Andreas Koch, Valerie Fritz, Arndt Hartmann, Anja Katrin Bosserhoff, Claus Hellerbrand
OBJECTIVE: Sorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC...
December 23, 2017: Gut
https://www.readbyqxmd.com/read/29273632/oncogenic-ras-isoforms-signaling-specificity-at-the-membrane
#17
REVIEW
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
How do Ras isoforms attain oncogenic specificity at the membrane? Oncogenic KRas, HRas, and NRas (K-Ras, H-Ras, and N-Ras) differentially populate distinct cancers. How they selectively activate effectors and why is KRas4B the most prevalent are highly significant questions. Here, we consider determinants that may bias isoform-specific effector activation and signaling at the membrane. We merge functional data with a conformational view to provide mechanistic insight. Cell-specific expression levels, pathway cross-talk, and distinct interactions are the key, but conformational trends can modulate selectivity...
December 22, 2017: Cancer Research
https://www.readbyqxmd.com/read/29273451/loss-of-pten-and-activation-of-kras-synergistically-induce-formation-of-intraductal-papillary-mucinous-neoplasia-from-pancreatic-ductal-cells-in-mice
#18
Janel L Kopp, Claire L Dubois, David F Schaeffer, Atefeh Samani, Farnaz Taghizadeh, Robert W Cowan, Andrew D Rhim, Bangyan L Stiles, Mark Valasek, Maike Sander
BACKGROUND & AIMS: Intraductal papillary mucinous neoplasias (IPMN) are precancerous cystic lesions that can develop into pancreatic ductal adenocarcinomas (PDACs). These large macroscopic lesions are frequently detected during medical imaging, but it is unclear how they form or progress to PDAC. We aimed to identify cells that form IPMNs and mutations that promote IPMN development and progression. METHODS: We generated mice with disruption of Pten specifically in ductal cells (Sox9CreERT2;Ptenflox/flox;R26RYFP or PtenΔDuct/ΔDuct mice) and used PtenΔDuct/+ and Pten+/+ mice as controls...
December 19, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29261009/small-change-big-effect-taking-ras-by-the-tail-through-suppression-of-post-prenylation-carboxylmethylation
#19
Hiu Yeung Lau, Mei Wang
Mutant RAS isoforms are the most common oncogenes affecting human cancers. After decades of effort in developing drugs targeting oncogenic RAS-driven cancers, we are still charting an unclear path. Despite recent developments exemplified by KRAS (G12C) inhibitors, direct targeting of mutant RAS remains a difficult endeavor. Inhibiting RAS function by targeting its post-translational prenylation processing has remained an important approach, especially with recent progress on the study of isoprenylcysteine carboxylmethyltransferase (ICMT), the unique enzyme for the last step of prenylation processing of RAS isoforms and other substrates...
December 20, 2017: Small GTPases
https://www.readbyqxmd.com/read/29259247/ras-pathway-mutation-patterns-define-epigenetic-subclasses-in-juvenile-myelomonocytic-leukemia
#20
Daniel B Lipka, Tania Witte, Reka Toth, Jing Yang, Manuel Wiesenfarth, Peter Nöllke, Alexandra Fischer, David Brocks, Zuguang Gu, Jeongbin Park, Brigitte Strahm, Marcin Wlodarski, Ayami Yoshimi, Rainer Claus, Michael Lübbert, Hauke Busch, Melanie Boerries, Mark Hartmann, Maximilian Schönung, Umut Kilik, Jens Langstein, Justyna A Wierzbinska, Caroline Pabst, Swati Garg, Albert Catalá, Barbara De Moerloose, Michael Dworzak, Henrik Hasle, Franco Locatelli, Riccardo Masetti, Markus Schmugge, Owen Smith, Jan Stary, Marek Ussowicz, Marry M van den Heuvel-Eibrink, Yassen Assenov, Matthias Schlesner, Charlotte Niemeyer, Christian Flotho, Christoph Plass
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome...
December 19, 2017: Nature Communications
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