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Kras lung cancer

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https://www.readbyqxmd.com/read/29233960/multiplexed-in-vivo-homology-directed-repair-and-tumor-barcoding-enables-parallel-quantification-of-kras-variant-oncogenicity
#1
Ian P Winters, Shin-Heng Chiou, Nicole K Paulk, Christopher D McFarland, Pranav V Lalgudi, Rosanna K Ma, Leszek Lisowski, Andrew J Connolly, Dmitri A Petrov, Mark A Kay, Monte M Winslow
Large-scale genomic analyses of human cancers have cataloged somatic point mutations thought to initiate tumor development and sustain cancer growth. However, determining the functional significance of specific alterations remains a major bottleneck in our understanding of the genetic determinants of cancer. Here, we present a platform that integrates multiplexed AAV/Cas9-mediated homology-directed repair (HDR) with DNA barcoding and high-throughput sequencing to simultaneously investigate multiple genomic alterations in de novo cancers in mice...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29229669/kras-the-critical-driver-and-therapeutic-target-for-pancreatic-cancer
#2
Andrew M Waters, Channing J Der
RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in human cancer. With the highest RAS mutation frequencies seen with the top three causes of cancer deaths in the United States (lung, colorectal, and pancreatic cancer), the development of anti-RAS therapies is a major priority for cancer research. Despite more than three decades of intense effort, no effective RAS inhibitors have yet to reach the cancer patient. With bitter lessons learned from past failures and with new ideas and strategies, there is renewed hope that undruggable RAS may finally be conquered...
December 11, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29228562/clinical-mutational-profiling-of-1006-lung-cancers-by-next-generation-sequencing
#3
Peter B Illei, Deborah Belchis, Li-Hui Tseng, Doreen Nguyen, Federico De Marchi, Lisa Haley, Stacy Riel, Katie Beierl, Gang Zheng, Julie R Brahmer, Frederic B Askin, Christopher D Gocke, James R Eshleman, Patrick M Forde, Ming-Tseh Lin
Analysis of lung adenocarcinomas for actionable mutations has become standard of care. Here, we report our experience using next generation sequencing (NGS) to examine AKT1, BRAF, EGFR, ERBB2, KRAS, NRAS, and PIK3CA genes in 1006 non-small cell lung cancers in a clinical diagnostic setting. NGS demonstrated high sensitivity. Among 760 mutations detected, the variant allele frequency (VAF) was 2-5% in 33 (4.3%) mutations and 2-10% in 101 (13%) mutations. A single bioinformatics pipeline using Torrent Variant Caller, however, missed a variety of EGFR mutations...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29223537/rankl-signaling-sustains-primary-tumor-growth-in-genetically-engineered-mouse-models-of-lung-adenocarcinoma
#4
Julien Faget, Caroline Contat, Nadine Zangger, Solange Peters, Etienne Meylan
HYPOTHESIS: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-κB (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy. METHODS: RANK and RANKL expression in human lung adenocarcinoma was interrogated from publicly available gene expression datasets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using micro-computed tomography...
December 6, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29219616/next-generation-sequencing-approach-to-non-small-cell-lung-carcinoma-yields-more-actionable-alterations
#5
Mitra Mehrad, Somak Roy, Humberto Trejo Bittar, Sanja Dacic
CONTEXT: - Different testing algorithms and platforms for EGFR mutations and ALK rearrangements in advanced-stage lung adenocarcinoma exist. The multistep approach with single-gene assays has been challenged by more efficient next-generation sequencing (NGS) of a large number of gene alterations. The main criticism of the NGS approach is the detection of genomic alterations of uncertain significance. OBJECTIVE: - To determine the best testing algorithm for patients with lung cancer in our clinical practice...
December 8, 2017: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/29212306/oncogene-driven-metabolic-alterations-in-cancer
#6
REVIEW
Hye-Young Min, Ho-Young Lee
Cancer is the leading cause of human deaths worldwide. Understanding the biology underlying the evolution of cancer is important for reducing the economic and social burden of cancer. In addition to genetic aberrations, recent studies demonstrate metabolic rewiring, such as aerobic glycolysis, glutamine dependency, accumulation of intermediates of glycolysis, and upregulation of lipid and amino acid synthesis, in several types of cancer to support their high demands on nutrients for building blocks and energy production...
December 7, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/29211816/clinical-outcome-and-molecular-characterisation-of-chemorefractory-metastatic-colorectal-cancer-patients-with-long-term-efficacy-of-regorafenib-treatment
#7
Erika Martinelli, Vincenzo Sforza, Claudia Cardone, Anna Capasso, Anna Nappi, Giulia Martini, Stefania Napolitano, Anna Maria Rachiglio, Nicola Normanno, Salvatore Cappabianca, Alfonso Reginelli, Maurizio Di Bisceglie, Tiziana Pia Latiano, Evaristo Maiello, Michele Orditura, Fernando De Vita, Floriana Morgillo, Fortunato Ciardiello, Teresa Troiani
HASH(0x4a0b560) Background: To investigate the potential predictors of response to regorafenib, in chemorefractory metastatic colorectal cancer (mCRC) patients with long-term efficacy from regorafenib treatment. Methods: Retrospective, single institution analysis of patients with chemorefractory mCRC treated with regorafenib, in clinical practice setting. 123 patients were treated and stratified into two groups according to number of cycles received (<7 and ≥7)...
2017: ESMO Open
https://www.readbyqxmd.com/read/29208669/vimentin-is-required-for-lung-adenocarcinoma-metastasis-via-heterotypic-tumor-cell-cancer-associated-fibroblast-interactions-during-collective-invasion
#8
Alessandra M Richardson, Lauren Havel, Allyson E Koyen, Jessica M Konen, John A Shupe, W G Wiles, W David Martin, Hans Grossniklaus, Gabriel L Sica, Melissa Gilbert-Ross, Adam Marcus
PURPOSE: Vimentin is an epithelial to mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis. EXPERIMENTAL DESIGN: We used the LSL-Kras G12D/Lkb1 fl/fl/Vim-/-model (KLV-/-), which incorporates a whole-body knockout of vimentin and is derived from the Cre-dependent LSL-Kras G12D/Lkb1 fl/fl model (KLV+/+)...
December 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29203670/kras-mutant-genetically-engineered-mouse-models-of-human-cancers-are-genomically-heterogeneous
#9
Wei-Jen Chung, Anneleen Daemen, Jason H Cheng, Jason E Long, Jonathan E Cooper, Bu-Er Wang, Christopher Tran, Mallika Singh, Florian Gnad, Zora Modrusan, Oded Foreman, Melissa R Junttila
KRAS mutant tumors are largely recalcitrant to targeted therapies. Genetically engineered mouse models (GEMMs) of Kras mutant cancer recapitulate critical aspects of this disease and are widely used for preclinical validation of targets and therapies. Through comprehensive profiling of exomes and matched transcriptomes of >200 KrasG12D-initiated GEMM tumors from one lung and two pancreatic cancer models, we discover that significant intratumoral and intertumoral genomic heterogeneity evolves during tumorigenesis...
December 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29199670/targeted-therapy-in-nonsmall-cell-lung-cancer
#10
REVIEW
T Puri
Activating mutations in the epidermal growth factor receptor gene and rearrangement of the anaplastic lymphoma kinase gene exemplify the molecular characterization of nonsmall cell lung cancer (NSCLC), particularly adenocarcinoma, and its therapeutic relevance. Several genetic alterations with prognostic and predictive role, including ROS, RET, MET, KRAS, have now been identified in adenocarcinoma and some such as DDR2 and fibroblast growth factor receptor 1 in squamous cell carcinoma. This has heralded the development of agents targeted against these aberrations...
January 2017: Indian Journal of Cancer
https://www.readbyqxmd.com/read/29198084/-the-impact-of-molecular-profiling-using-next-generation-sequencing-in-advanced-lung-cancer
#11
Anna Belilovski Rozenblum, Maya Ilouze, Elizabeth Dudnik, Lior Soussan-Gutman, Addie Dvir, Nir Peled
BACKGROUND: In the last decade, important advances in understanding the lung cancer cellular signal pathways have led to the designing of targeted drugs that significantly prolong survival. Recent data shows that 64% of lung adenocarcinomas harbor at least one activating driver mutation, including treatable mutations such as RET, ERBB2 (HER-2) and ROS1 gene mutations, besides the regularly screened ALK and EGFR genes. Next-Generation Sequencing (NGS) reveals more clinically meaningful genomic alterations as compared to currently used diagnostic tests...
November 2017: Harefuah
https://www.readbyqxmd.com/read/29196555/ral-gtpases-biology-and-potential-as-therapeutic-targets-in-cancer
#12
REVIEW
Chao Yan, Dan Theodorescu
More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, HRAS, KRAS, and NRAS being the commonly mutated in tumors. These RAS mutations, most often functionally activating, are especially common in pancreatic, lung, and colorectal cancers. Efforts to inhibit RAS and related GTPases have produced inhibitors targeting the downstream effectors of RAS signaling, including inhibitors of the RAF-mitogen-activated protein kinase/extracellular signal-related kinase (ERK)-ERK kinase pathway and the phosphoinositide-3-kinase-AKT-mTOR kinase pathway...
January 2018: Pharmacological Reviews
https://www.readbyqxmd.com/read/29191602/lkb1-stk11-mutations-in-non-small-cell-lung-cancer-patients-descriptive-analysis-and-prognostic-value
#13
Francesco Facchinetti, Maria Virginia Bluthgen, Gabrielle Tergemina-Clain, Laura Faivre, Jean-Pierre Pignon, David Planchard, Jordi Remon, Jean-Charles Soria, Ludovic Lacroix, Benjamin Besse
BACKGROUND: LKB1/STK11 (STK11) is among the most inactivated tumor-suppressor genes in non-small cell lung cancer (NSCLC). While evidence concerning the biologic role of STK11 is accumulating, its prognostic significance in advanced NSCLC has not been envisaged yet. MATERIALS AND METHODS: This retrospective analysis included consecutive NSCLC patients with available STK11 information who underwent a platinum-based chemotherapy. STK11 mutational status was correlated to clinico-pathological and mutational features...
October 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29191600/mig-6-deficiency-cooperates-with-oncogenic-kras-to-promote-mouse-lung-tumorigenesis
#14
Jian Liu, Sung-Nam Cho, San-Pin Wu, Nili Jin, Seyed Javad Moghaddam, Jennifer L Gilbert, Ignacio Wistuba, Francesco J DeMayo
OBJECTIVES: Lung cancer is the leading cause of cancer related deaths worldwide and mutation activating KRAS is one of the most frequent mutations found in lung adenocarcinoma. Identifying regulators of KRAS may aid in the development of therapies to treat this disease. The mitogen-induced gene 6, MIG-6, is a small adaptor protein modulating signaling in cells to regulate the growth and differentiation in multiple tissues. Here, we investigated the role of Mig-6 in regulating adenocarcinoma progression in the lungs of genetically engineered mice with activation of Kras...
October 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29191596/pd-l1-expression-in-advanced-nsclc-insights-into-risk-stratification-and-treatment-selection-from-a-systematic-literature-review
#15
REVIEW
Robert Brody, Yiduo Zhang, Marc Ballas, Mohd Kashif Siddiqui, Palvi Gupta, Craig Barker, Anita Midha, Jill Walker
Tumors can evade immune detection by exploiting inhibitory immune checkpoints such as the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway. Antibodies that block this pathway offer a promising new approach to treatment in advanced/metastatic non-small cell lung cancer (NSCLC). A systematic review of the literature was conducted to assess the association of PD-L1 with important patient and disease characteristics, the prognostic significance of PD-L1 expressing NSCLC tumors, and the value of PD-L1 as a predictive biomarker of response to anti-PD-1/PD-L1 treatments in advanced/metastatic NSCLC...
October 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29190947/thioredoxin-system-mediated-regulation-of-mutant-kras-associated-pancreatic-neoplasia-and-cancer
#16
Michelle A Schultz, Andrew M Diaz, Sharon Smite, Anna R Lay, Brian DeCant, Ronald McKinney, Windel E Mascarinas, Yinglin Xia, Carola Neumann, David Bentrem, David W Dawson, Paul J Grippo
Peroxiredoxin-1 (Prdx1), a member of the thioredoxin (Txn) system, is overexpressed and correlates with poor prognosis in pancreatic cancer patients and can suppress Kras signaling through redox-mediated inhibition of ERK and AKT in lung and breast cancer. Its redox function is maintained by Txn and sulfiredoxin (Srxn), and its tumor promoting functions are activated by post-translational modification. We studied the role of the Txn system in pancreatic neoplasia and cancer by determining how it regulates the phosphorylation of Kras effectors and by determining its association with patient survival...
November 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29186353/prevalence-and-clinical-association-of-gene-mutations-through-multiplex-mutation-testing-in-patients-with-nsclc-results-from-the-etop-lungscape-project
#17
K M Kerr, U Dafni, K Schulze, E Thunnissen, L Bubendorf, H Hager, S Finn, W Biernat, L Vliegen, J H Losa, A Marchetti, R Cheney, A Warth, E-J Speel, F Blackhall, K Monkhorst, E Jantus Lewintre, V Tischler, C Clark, J Bertran-Alamillo, P Meldgaard, K Gately, A Wrona, P Vandenberghe, E Felip, G De Luca, S Savic, T Muley, E F Smit, A-M C Dingemans, L Priest, P Baas, C Camps, W Weder, V Polydoropoulou, T R Geiger, R Kammler, T Sumiyoshi, M A Molina, D S Shames, R A Stahel, S Peters
Background: Reported prevalence of driver gene mutations in non-small cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the ETOP Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathological features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically-annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform...
November 23, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29184677/cell-free-dna-analysis-by-sire%C3%A2-next-generation-sequencing-panel-in-non-small-cell-lung-cancer-patients-focus-on-basal-setting
#18
Pasquale Pisapia, Francesco Pepe, Riccardo Smeraglio, Maria Russo, Danilo Rocco, Roberta Sgariglia, Mariantonia Nacchio, Caterina De Luca, Elena Vigliar, Claudio Bellevicine, Giancarlo Troncone, Umberto Malapelle
Background: Non small cell lung cancer (NSCLC) is diagnosed in most cases on small tissue samples, such as cytological preparations and histological biopsies; these limited tissue specimens may be not always sufficient for testing epidermal growth factor receptor (EGFR) mutations and other relevant predictive biomarkers. Cell-free DNA (cfDNA) can be used as a surrogate for EGFR mutational testing, whenever tissue is unavailable. However, the detection of gene mutations on cfDNA is challenging; in fact, the extremely low concentration of circulating tumor DNA requires the implementation of highly sensitive and validated next generation techniques...
October 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/29184501/identification-of-a-new-potent-inhibitor-targeting-kras-in-non-small-cell-lung-cancer-cells
#19
Chun Xie, Ying Li, Lan-Lan Li, Xing-Xing Fan, Yu-Wei Wang, Chun-Li Wei, Liang Liu, Elaine Lai-Han Leung, Xiao-Jun Yao
KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is an oncogenic driver with mutations in 30% of non-small cell lung cancer (NSCLC). However, there is no effective clinical drug even though it has been identified as an oncogene for 30 years. In this study, we identified a small molecule inhibitor compound 0375-0604 targeting KRAS by using molecular docking based virtual screening approach. Compound 0375-0604 had a good binding affinity to KRAS in vitro and exhibited cytotoxicity in oncogenic KRAS expressing NSCLC cell lines...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29184034/mek-inhibitor-trametinib-does-not-prevent-the-growth-of-anaplastic-lymphoma-kinase-alk-addicted-neuroblastomas
#20
Ganesh Umapathy, Jikui Guan, Dan E Gustafsson, Niloufar Javanmardi, Diana Cervantes-Madrid, Anna Djos, Tommy Martinsson, Ruth H Palmer, Bengt Hallberg
Activation of the RAS-RAF-MEK-ERK signaling pathway is implicated in driving the initiation and progression of multiple cancers. Several inhibitors targeting the RAS-MAPK pathway are clinically approved as single- or polyagent therapies for patients with specific types of cancer. One example is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK-positive, EGFR-activated, or KRAS-mutant lung cancers and neuroblastomas that also contain activating mutations in the RAS-MAPK pathway...
November 28, 2017: Science Signaling
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