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https://www.readbyqxmd.com/read/28650561/craniosynostosis-in-patients-with-rasopathies-accumulating-clinical-evidence-for-expanding-the-phenotype
#1
Kimiko Ueda, Masako Yaoita, Tetsuya Niihori, Yoko Aoki, Nobuhiko Okamoto
RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan-like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported...
June 26, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28649886/epidermal-growth-factor-inhibitors-in-first-line-for-metastatic-colorectal-cancer-with-ras-wild-type-a-perspective-based-on-pharmacological-costs
#2
Jacopo Giuliani, Andrea Bonetti
In light of the relevant expenses of pharmacological interventions it might be interesting to make a balance between the cost of the new drugs administered, such as EGFRIs (cetuximab and panitunumab) and the added value represented by the improvement of the clinical parameters of interest such as progression free survival (PFS). Areas Covered: The analysis was conducted to assess the effect of front-line chemotherapy on the PFS, separately, on each arm of the evaluated trials. Only phase III randomized controlled trials (RCTs) were considered...
June 24, 2017: Expert Review of Pharmacoeconomics & Outcomes Research
https://www.readbyqxmd.com/read/28646021/eif1ax-and-nras-mutations-co-occur-and-cooperate-in-low-grade-serous-ovarian-carcinomas
#3
Dariush Etemadmoghadam, Walid J Azar, Ying Lei, Tania Moujaber, Dale W Garsed, Catherine Kennedy, Sian Fereday, Chris Mitchell, Yoke-Eng Chiew, Joy Hendley, Australian Ovarian Cancer Study Group, Raghwa Sharma, Paul Harnett, Jason Li, Elizabeth L Christie, Ann-Marie Patch, Joshy George, George Au-Yeung, Gisela Mir Arnau, Timothy P Holloway, Timothy Semple, John V Pearson, Nicola Waddell, Sean Grimmond, Martin Köbel, Helen Rizos, Ivan Lomakin, David D L Bowtell, Anna DeFazio
Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF and NRAS. RAS pathway mutations were mutually exclusive, however we found significant co-occurrence of mutations in NRAS and EIF1AX Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity...
June 23, 2017: Cancer Research
https://www.readbyqxmd.com/read/28634423/tumor-ras-gene-expression-levels-are-influenced-by-the-mutational-status-of-ras-genes-and-both-upstream-and-downstream-ras-pathway-genes
#4
Robert M Stephens, Ming Yi, Bailey Kessing, Dwight V Nissley, Frank McCormick
The 3 human RAS genes play pivotal roles regulating proliferation, differentiation, and survival in normal cells and become mutated in 15% to 20% of all human tumors and amplified in many others. In this report, we examined data from The Cancer Genome Atlas to investigate the relationship between RAS gene mutational status and messenger RNA expression. We show that all 3 RAS genes exhibit increased expression when they are mutated in a context-dependent manner. In the case of KRAS, this increase is manifested by a larger proportional increase in KRAS4A than KRAS4B, although both increase significantly...
2017: Cancer Informatics
https://www.readbyqxmd.com/read/28633089/first-line-panitumumab-plus-folfox4-or-folfiri-in-colorectal-cancer-with-multiple-or-unresectable-liver-metastases-a-randomised-phase-ii-trial-planet-ttd
#5
Alfredo Carrato, Albert Abad, Bartomeu Massuti, Cristina Grávalos, Pilar Escudero, Federico Longo-Muñoz, José-Luis Manzano, Auxiliadora Gómez, María José Safont, Javier Gallego, Beatriz García-Paredes, Carles Pericay, Rosario Dueñas, Fernando Rivera, Ferrán Losa, Manuel Valladares-Ayerbes, Encarnación González, Enrique Aranda
BACKGROUND: In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations. METHODS: Multicentre, open-label study in untreated patients ≥ 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI...
June 17, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28623374/nucleotide-based-covalent-inhibitors-of-kras-can-only-be-efficient-in-vivo-if-they-bind-reversibly-with-gtp-like-affinity
#6
Matthias P Müller, Sadasivam Jeganathan, Angelika Heidrich, Jeremy Campos, Roger S Goody
Simple reversible competitive inhibition of nucleotide binding of GTP to Ras family GTPases has long been recognized as an unlikely approach to manipulating the activity of such proteins for experimental or therapeutic purposes. This is due to the high affinity of GTP to GTPases coupled with high cellular GTP concentrations, but also to problems of specificity for the highly conserved binding sites in GTPases. A recent approach suggested that these problems might be overcome by using GDP derivatives that can undergo a covalent reaction with disease specific mutants, in particular addressing inhibition of KRasG12C using GDP equipped with an electrophilic group at the β-phosphate...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28623230/flexible-body-motions-of-calmodulin-and-the-farnesylated-hypervariable-region-yield-a-high-affinity-interaction-enabling-k-ras4b-membrane-extraction
#7
Hyunbum Jang, Avik Banerjee, Tanmay Chavan, Vadim Gaponenko, Ruth Nussinov
In calmodulin (CaM)-rich environments, oncogenic KRAS plays a critical role in adenocarcinomas by promoting PI3K/Akt signaling. We previously proposed that at elevated calcium levels in cancer, CaM recruits PI3Kα to the membrane and extracts K-Ras4B from the membrane, organizing a K-Ras4B/CaM/PI3Kα ternary complex. CaM can thereby replace a missing receptor tyrosine kinase signal to fully activate PI3Kα. Recent experimental data show that CaM selectively promotes K-Ras signaling, but not of N-Ras or H-Ras...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28621837/pediatric-follicular-thyroid-carcinoma-indolent-cancer-with-low-prevalence-of-ras-mutations-and-absence-of-pax8-pparg-fusion-in-a-japanese-population
#8
Huy Gia Vuong, Tetsuo Kondo, Naoki Oishi, Tadao Nakazawa, Kunio Mochizuki, Akira Miyauchi, Mitsuyoshi Hirokawa, Ryohei Katoh
BACKGROUND: Pediatric follicular thyroid carcinomas are uncommon and their clinicopathological features and molecular profiles are still unknown. In this present study, we aimed to investigate the clinicopathological aspects of a large series of follicular thyroid carcinomas (FTCs) in pediatric patients and to analyse the point mutations in codons 12, 13 and 61 of NRAS, HRAS and KRAS genes and the rearrangements of PAX8-PPARG. METHODS: A total of 41 pediatric FTCs less than 21 years of age were enrolled in the present study...
June 16, 2017: Histopathology
https://www.readbyqxmd.com/read/28618430/extreme-assay-sensitivity-in-molecular-diagnostics-further-unveils-intratumour-heterogeneity-in-metastatic-colorectal-cancer-as-well-as-artifactual-low-frequency-mutations-in-the-kras-gene
#9
Sara Mariani, Luca Bertero, Simona Osella-Abate, Cristiana Di Bello, Paola Francia di Celle, Vittoria Coppola, Anna Sapino, Paola Cassoni, Caterina Marchiò
BACKGROUND: Gene mutations in the RAS family rule out metastatic colorectal carcinomas (mCRCs) from anti-EGFR therapies. METHODS: We report a retrospective analysis by Sequenom Massarray and fast COLD-PCR followed by Sanger sequencing on 240 mCRCs. RESULTS: By Sequenom, KRAS and NRAS exons 2-3-4 were mutated in 52.9% (127/240) of tumours, while BRAF codon 600 mutations reached 5% (12/240). Fast COLD-PCR found extra mutations at KRAS exon 2 in 15/166 (9%) of samples, previously diagnosed by Sequenom as wild-type or mutated at RAS (exons 3-4) or BRAF genes...
June 15, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28618197/analysis-of-mutant-allele-fractions-in-driver-genes-in-colorectal-cancer-biological-and-clinical-insights
#10
Rodrigo Dienstmann, Elena Elez, Guillem Argiles, Ignacio Matos, Enrique Sanz-Garcia, Carolina Ortiz, Teresa Macarulla, Jaume Capdevila, Maria Alsina, Tamara Sauri, Helena Verdaguer, Marta Vilaro, Fiorella Ruiz-Pace, Cristina Viaplana, Ariadna Garcia, Stefania Landolfi, Hector G Palmer, Paolo Nuciforo, Jordi Rodon, Ana Vivancos, Josep Tabernero
Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Out of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors) or PIK3CA mutations (PI3K pathway inhibitors)...
June 15, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28615361/targeting-kras-dependent-tumors-with-azd4785-a-high-affinity-therapeutic-antisense-oligonucleotide-inhibitor-of-kras
#11
Sarah J Ross, Alexey S Revenko, Lyndsey L Hanson, Rebecca Ellston, Anna Staniszewska, Nicky Whalley, Sanjay K Pandey, Mitchell Revill, Claire Rooney, Linda K Buckett, Stephanie K Klein, Kevin Hudson, Brett P Monia, Michael Zinda, David C Blakey, Paul D Lyne, A Robert Macleod
Activating mutations in KRAS underlie the pathogenesis of up to 20% of human tumors, and KRAS is one of the most frequently mutated genes in cancer. Developing therapeutics to block KRAS activity has proven difficult, and no direct inhibitor of KRAS function has entered clinical trials. We describe the preclinical evaluation of AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting KRAS mRNA. AZD4785 potently and selectively depleted cellular KRAS mRNA and protein, resulting in inhibition of downstream effector pathways and antiproliferative effects selectively in KRAS mutant cells...
June 14, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28597297/intrinsic-protein-disorder-in-oncogenic-kras-signaling
#12
REVIEW
Ruth Nussinov, Hyunbum Jang, Chung-Jung Tsai, Tsung-Jen Liao, Shuai Li, David Fushman, Jian Zhang
How Ras, and in particular its most abundant oncogenic isoform K-Ras4B, is activated and signals in proliferating cells, poses some of the most challenging questions in cancer cell biology. In this paper, we ask how intrinsically disordered regions in K-Ras4B and its effectors help promote proliferative signaling. Conformational disorder allows spanning long distances, supports hinge motions, promotes anchoring in membranes, permits segments to fulfil multiple roles, and broadly is crucial for activation mechanisms and intensified oncogenic signaling...
June 8, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28596502/correlation-between-mek-signature-and-ras-gene-alteration-in-advanced-gastric-cancer
#13
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...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28594589/mek-inhibitors-in-oncology-a-patent-review-2015-present
#14
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/28594414/genotype-and-phenotype-spectrum-of-nras-germline-variants
#15
Franziska Altmüller, Christina Lissewski, Debora Bertola, Elisabetta Flex, Zornitza Stark, Stephanie Spranger, Gareth Baynam, Michelle Buscarilli, Sarah Dyack, Jane Gillis, Helger G Yntema, Francesca Pantaleoni, Rosa LE van Loon, Sara MacKay, Kym Mina, Ina Schanze, Tiong Yang Tan, Maie Walsh, Susan M White, Marena R Niewisch, Sixto García-Miñaúr, Diego Plaza, Mohammad Reza Ahmadian, Hélène Cavé, Marco Tartaglia, Martin Zenker
RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants)...
June 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28581519/autophagy-suppresses-ras-driven-epithelial-tumourigenesis-by-limiting-the-accumulation-of-reactive-oxygen-species
#16
J Manent, S Banerjee, R de Matos Simoes, T Zoranovic, C Mitsiades, J M Penninger, K J Simpson, P O Humbert, H E Richardson
Activation of Ras signalling occurs in ~30% of human cancers; however, activated Ras alone is not sufficient for tumourigenesis. In a screen for tumour suppressors that cooperate with oncogenic Ras (Ras(V12)) in Drosophila, we identified genes involved in the autophagy pathway. Bioinformatic analysis of human tumours revealed that several core autophagy genes, including GABARAP, correlate with oncogenic KRAS mutations and poor prognosis in human pancreatic cancer, supporting a potential tumour-suppressive effect of the pathway in Ras-driven human cancers...
June 5, 2017: Oncogene
https://www.readbyqxmd.com/read/28581516/pancreatic-cancer-heterogeneity-and-response-to-mek-inhibition
#17
K Pedersen, F Bilal, C Bernadó Morales, M T Salcedo, T Macarulla, D Massó-Vallés, V Mohan, A Vivancos, M-J Carreras, X Serres, M Abu-Suboh, J Balsells, E Allende, I Sagi, L Soucek, J Tabernero, J Arribas
Our increasing knowledge of the mechanisms behind the progression of pancreatic cancer (PC) has not yet translated into effective treatments. Many promising drugs have failed in the clinic, highlighting the need for better preclinical models to assess drug efficacy and characterize mechanisms of resistance. Using different experimental models, including patient-derived xenografts (PDXs), we gauged the efficacy of therapies aimed at two hallmark lesions of PCs: activation of signaling pathways by oncogenic KRAS and inactivation of tumor-suppressor genes...
June 5, 2017: Oncogene
https://www.readbyqxmd.com/read/28576857/braf-mutations-as-predictive-biomarker-for-response-to-anti-egfr-monoclonal-antibodies
#18
Emilie M J van Brummelen, Anthonius de Boer, Jos H Beijnen, Jan H M Schellens
Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer could be treated with anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab only in absence of Rat-Sarcoma (RAS) mutations. In addition to the previously established biomarker Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, cumulative evidence also shows that patients whose tumors harbor KRAS exons 3 or 4 and neuroblastoma rat-sarcoma viral oncogene homolog (NRAS) exons 2, 3, and 4 mutations are found unlikely to benefit from anti-EGFR treatment...
June 2, 2017: Oncologist
https://www.readbyqxmd.com/read/28566436/reactivation-of-the-p90rsk-cdc25c-pathway-leads-to-bypass-of-the-ganetespib-induced-g2-m-arrest-and-mediates-acquired-resistance-to-ganetespib-in-kras-mutant-nsclc
#19
Suman Chatterjee, Eric H-B Huang, Ian Christie, Timothy F Burns
A subset of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations including the most frequently observed driver mutant KRAS which is associated with a poor prognosis.   As direct RAS targeting in the clinic has been unsuccessful to date, use of Heat shock protein 90 (Hsp90) inhibitors appeared to be a promising therapy for KRAS mutant NSCLC, however limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit...
May 31, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28560458/epha2-receptor-activation-with-ephrin-a1-ligand-restores-cetuximab-efficacy-in-nras-mutant-colorectal-cancer-cells
#20
Elisabet Cuyàs, Bernardo Queralt, Begoña Martin-Castillo, Joaquim Bosch-Barrera, Javier A Menendez
Patients with wild-type KRAS metastatic colorectal cancer (mCRC) that harbors NRAS activating mutations do not benefit from anti-EGFR therapies. Very little is known about oncogenic NRAS signaling driving mCRC unresponsiveness to the EGFR-directed antibody cetuximab. Using a system of paired NRAS-mutant and wild-type isogenic mCRC cell lines to explore signaling pathways engaged by the common oncogenic NRAS Q61K variant upon challenge with cetuximab, we uncovered an unexpected mechanism of resistance to cetuximab involving dysregulation of the ephrin-A1/EphA2 signaling axis...
May 30, 2017: Oncology Reports
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