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https://www.readbyqxmd.com/read/29469192/gata6-positive-lung-adenocarcinomas-are-associated-with-invasive-mucinous-adenocarcinoma-morphology-hnf4%C3%AE-expression-and-kras-mutations
#1
Naoki Nakajima, Akihiko Yoshizawa, Tomoyuki Nakajima, Masahiro Hirata, Ayako Furuhata, Shinji Sumiyoshi, Mariyo Rokutan-Kurata, Makoto Sonobe, Toshi Menju, Ei Miyamoto, Toyofumi F Chen-Yoshikawa, Hiroshi Date, Hironori Haga
AIMS: GATA6 is known to play a role in lung development. However, its role in the carcinogenesis of lung cancer is not well studied. The aim of this study was to analyze GATA6 expression in lung adenocarcinomas (LA) by immunohistochemistry (IHC) to define its association with clinicopathological characteristics. METHODS AND RESULTS: IHC analysis of GATA6 was performed using tissue microarray slides containing 348 LAs. The association between GATA6 expression and clinicopathological parameters was evaluated...
February 22, 2018: Histopathology
https://www.readbyqxmd.com/read/29464758/a-genomic-and-clinicopathologic-study-of-non-small-cell-lung-cancers-with-discordant-ros1-gene-status-by-fluorescent-in-situ-hybridization-and-immunohistochemical-analysis
#2
Jing Zhao, Xiaotong Chen, J Zheng, M Kong, B Wang, W Ding
BACKGROUND: ROS1 immunohistochemistry (IHC) using D4D6 antibody is a useful tool for screening patients with non-small cell lung cancer (NSCLC) slated for targeted therapy. Many studies and our data have identified cases that express the ROS1 protein strongly but are negative for ROS1 by fluorescent in situ hybridization (FISH). The present study investigated the driver mutation and clinicopathologic characteristics of 26 discordant cases (ROS1 IHC-positive but FISH-negative) to find new clues for distinguishing real ROS1-rearranged cases...
February 21, 2018: Histopathology
https://www.readbyqxmd.com/read/29464099/implications-of-kras-mutations-in-acquired-resistance-to-treatment-in-nsclc
#3
REVIEW
Marzia Del Re, Eleonora Rofi, Giuliana Restante, Stefania Crucitta, Elena Arrigoni, Stefano Fogli, Massimo Di Maio, Iacopo Petrini, Romano Danesi
Rationale: KRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29455666/kras-oncogene-in-non-small-cell-lung-cancer-clinical-perspectives-on-the-treatment-of-an-old-target
#4
REVIEW
Marta Román, Iosune Baraibar, Inés López, Ernest Nadal, Christian Rolfo, Silvestre Vicent, Ignacio Gil-Bazo
Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed...
February 19, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29455644/mir-19b-enhances-proliferation-and-apoptosis-resistance-via-the-egfr-signaling-pathway-by-targeting-pp2a-and-bim-in-non-small-cell-lung-cancer
#5
Ulrich Baumgartner, Fabienne Berger, Ali Hashemi Gheinani, Sabrina Sofia Burgener, Katia Monastyrskaya, Erik Vassella
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations enable constitutive active downstream signaling of PI3K/AKT, KRAS/ERK and JAK/STAT pathways, and promote tumor progression by inducing uncontrolled proliferation, evasion of apoptosis and migration of non-small cell lung cancer (NSCLC). In addition, such EGFR mutations increase the susceptibility of patients with NSCLC to tyrosine kinase inhibitor (TKI) therapy, but treated patients will invariably relapse with resistant disease...
February 19, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29454261/frequency-of-somatic-tp53-mutations-in-combination-with-known-pathogenic-mutations-in-colon-adenocarcinoma-non-small-cell-lung-carcinoma-and-gliomas-as-identified-by-next-generation-sequencing
#6
Zahra Shajani-Yi, Francine B de Abreu, Jason D Peterson, Gregory J Tsongalis
The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer. It encodes p53, a DNA-binding transcription factor that regulates multiple genes involved in DNA repair, metabolism, cell cycle arrest, apoptosis, and senescence. TP53 is associated with human cancer by mutations that lead to a loss of wild-type p53 function as well as mutations that confer alternate oncogenic functions that enable them to promote invasion, metastasis, proliferation, and cell survival. Identifying the discrete TP53 mutations in tumor cells may help direct therapies that are more effective...
February 13, 2018: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29453361/heterogeneity-and-mutation-in-kras-and-associated-oncogenes-evaluating-the-potential-for-the-evolution-of-resistance-to-targeting-of-kras-g12c
#7
Vincent L Cannataro, Stephen G Gaffney, Carly Stender, Zi-Ming Zhao, Mark Philips, Andrew E Greenstein, Jeffrey P Townsend
Activating mutations in RAS genes are associated with approximately 20% of all human cancers. New targeted therapies show preclinical promise in inhibiting the KRAS G12C variant. However, concerns exist regarding the effectiveness of such therapies in vivo given the possibilities of existing intratumor heterogeneity or de novo mutation leading to treatment resistance. We performed deep sequencing of 27 KRAS G12-positive lung tumors to determine the prevalence of other oncogenic mutations within KRAS or within commonly mutated downstream genes that could confer resistance at the time of treatment...
February 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29447458/e-cadherin-loss-accelerates-tumor-progression-and-metastasis-in-a-mouse-model-of-lung-adenocarcinoma
#8
Kerstin W Sinkevicius, Kelly J Bellaria, Juliana Barrios, Patrizia Pessina, Manav Gupta, Christine Fillmore Brainson, Roderick T Bronson, Carla F Kim
Metastatic disease is the primary cause of death of lung cancer patients, but the mouse models of lung adenocarcinoma do not accurately recapitulate the tumor microenvironment or metastatic disease observed in patients. In this study, we conditionally deleted E-cadherin in an autochthonous lung adenocarcinoma mouse model driven by activated oncogenic Kras and p53 loss. Loss of E-cadherin significantly accelerated lung adenocarcinoma progression and decreased survival of the mice. Kras;p53;E-cadherin mice had a 41% lung tumor burden, invasive grade 4 tumors, and a desmoplastic stroma just 8 weeks after tumor initiation...
February 15, 2018: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29444439/differential-effector-engagement-by-oncogenic-kras
#9
Tina L Yuan, Arnaud Amzallag, Rachel Bagni, Ming Yi, Shervin Afghani, William Burgan, Nicole Fer, Leslie A Strathern, Katie Powell, Brian Smith, Andrew M Waters, David Drubin, Ty Thomson, Rosy Liao, Patricia Greninger, Giovanna T Stein, Ellen Murchie, Eliane Cortez, Regina K Egan, Lauren Procter, Matthew Bess, Kwong Tai Cheng, Chih-Shia Lee, Liam Changwoo Lee, Christof Fellmann, Robert Stephens, Ji Luo, Scott W Lowe, Cyril H Benes, Frank McCormick
KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3' kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29443392/spatial-aspects-of-oncogenic-signaling-determine-response-to-combination-therapy-in-slice-explants-from-kras-driven-lung-tumors
#10
Katja Närhi, Ashwini S Nagaraj, Elina Parri, Riku Turkki, Petra W van Duijn, Annabrita Hemmes, Jenni Lahtela, Virva Uotinen, Mikko I Mäyränpää, Kaisa Salmenkivi, Jari Räsänen, Nina Linder, Jan Trapman, Antti Rannikko, Olli Kallioniemi, Taija Af Hällström, Johan Lundin, Wolfgang Sommergruber, Simon Anders, Emmy W Verschuren
A key question in precision medicine is how functional heterogeneity in solid tumors informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signaling and therapy response can be modeled in precision-cut slices from Kras-driven non-small cell lung cancer (NSCLC) of varying histopathologies. Unexpectedly, profiling of in situ tumors demonstrates that signaling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma (ASC), and MAPK activity in adenocarcinoma (AC)...
February 14, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29440631/inhibition-of-kras-dependent-lung-cancer-cell-growth-by-deltarasin-blockage-of-autophagy-increases-its-cytotoxicity
#11
Elaine Lai Han Leung, Lian Xiang Luo, Zhong Qiu Liu, Vincent Kam Wai Wong, Lin Lin Lu, Ying Xie, Ni Zhang, Yuan Qing Qu, Xing Xing Fan, Ying Li, Min Huang, Dai Kai Xiao, Jun Huang, Yan Ling Zhou, Jian Xing He, Jian Ding, Xiao Jun Yao, David C Ward, Liang Liu
Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEδ interactions by binding to a hydrophobic pocket on PDEδ, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo...
February 13, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29437753/dynamic-changes-of-circulating-tumour-dna-in-surgical-lung-cancer-patients-protocol-for-a-prospective-observational-study
#12
Kezhong Chen, Heng Zhao, Fan Yang, Bengang Hui, Tianyang Wang, Lieu Tu Wang, Yanbin Shi, Jun Wang
INTRODUCTION: Circulating tumour DNA (ctDNA) has potential applications in cancer management. Most previous studies about ctDNA focused on advanced stage cancer patients. We have completed a clinical prospective study (NCT02645318) and showed the feasibility and clinical application of ctDNA detection in early stage non-small cell lung cancer (NSCLC) patients. The aim of this study is to investigate the elimination rate of ctDNA level after surgery. This is the first prospective study to evaluate the perioperative dynamic changes of ctDNA in surgical lung cancer patients...
February 6, 2018: BMJ Open
https://www.readbyqxmd.com/read/29434041/polo-like-kinase-4-inhibition-produces-polyploidy-and-apoptotic-death-of-lung-cancers
#13
Masanori Kawakami, Lisa Maria Mustachio, Lin Zheng, Yulong Chen, Jaime Rodriguez-Canales, Barbara Mino, Jonathan M Kurie, Jason Roszik, Pamela Andrea Villalobos, Kelsie L Thu, Jennifer Silvester, David W Cescon, Ignacio I Wistuba, Tak W Mak, Xi Liu, Ethan Dmitrovsky
Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication. CFI-400945 is a highly selective PLK4 inhibitor that deregulates centriole duplication, causing mitotic defects and death of aneuploid cancers. Prior work was substantially extended by showing CFI-400945 causes polyploidy, growth inhibition, and apoptotic death of murine and human lung cancer cells, despite expression of mutated KRAS or p53. Analysis of DNA content by propidium iodide (PI) staining revealed cells with >4N DNA content (polyploidy) markedly increased after CFI-400945 treatment...
February 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29415661/diethylnitrosamine-induces-lung-adenocarcinoma-in-fvb-n-mouse
#14
Zsolt Mervai, Krisztina Egedi, Ilona Kovalszky, Kornélia Baghy
BACKGROUND: Diethylnitrosamine is a well known carcinogen that induces cancers of various organs in mice and rats. Using FVB/N mouse strain, here we show that diethylnitrosamine induces primarily lung adenocarcinomas with modest tumor development in the liver, offering a new model to study chemical carcinogenesis in the lung. METHODS: Animals were exposed to a single high dose of diethylnitrosamine, and more than 70% of the mice developed lung cancer. To obtain a new transplantable tumor line, pieces of primary tumors were inoculated and maintained subcutaneously in the same mouse strain...
February 7, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29413057/tumor-biomarker-testing-in-non-small-cell-lung-cancer-a-decade-of-change
#15
Paul A VanderLaan, Deepa Rangachari, Adnan Majid, Mihir S Parikh, Sidharta P Gangadharan, Michael S Kent, Danielle C McDonald, Mark S Huberman, Susumu S Kobayashi, Daniel B Costa
INTRODUCTION: Although a growing list of essential genomic/immune-based biomarkers are linked to approved non-small-cell lung cancer (NSCLC) therapies worldwide, few reports have detailed the evolution of NSCLC predictive biomarker assessment in routine clinical practice. METHODS: We retrospectively reviewed the first one thousand plus NSCLC patient specimens from our institution analyzed for predictive biomarkers from 2004 to 2017 and evaluated patterns of testing as well as correlation with clinical-pathologic characteristics...
February 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29413048/distinct-clinicopathologic-features-genomic-characteristics-and-survival-of-central-and-peripheral-pulmonary-large-cell-neuroendocrine-carcinoma-from-different-origin-cells
#16
Fei Zhou, Likun Hou, Ting Ding, Quanming Song, Xiaoxia Chen, Chunxia Su, Wei Li, Guanghui Gao, Shengxiang Ren, Fengying Wu, Jiang Fan, Chunyan Wu, Jie Zhang, Caicun Zhou
BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) represents a rare entity in lung cancer with dismal prognosis. In the present study, we investigated whether there are significant differences between central and peripheral tumors of LCNEC, in terms of clinicopathologic features, genomic profiles, and survival. METHODS AND MATERIALS: A total of 126 cases of LCNEC were included. The tumors with invasion of the segmental and/or lobar bronchus were classified as central LCNEC and those without as peripheral LCNEC...
February 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29401004/molecular-testing-guideline-for-the-selection-of-patients-with-lung-cancer-for-treatment-with-targeted-tyrosine-kinase-inhibitors-american-society-of-clinical-oncology-endorsement-of-the-college-of-american-pathologists-international-association-for-the-study
#17
Gregory P Kalemkerian, Navneet Narula, Erin B Kennedy, William A Biermann, Jessica Donington, Natasha B Leighl, Madelyn Lew, James Pantelas, Suresh S Ramalingam, Martin Reck, Anjali Saqi, Michael Simoff, Navneet Singh, Baskaran Sundaram
Purpose In response to advances in the field, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) recently updated their recommendations for molecular testing for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations...
February 5, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29398453/updated-molecular-testing-guideline-for-the-selection-of-lung-cancer-patients-for-treatment-with-targeted-tyrosine-kinase-inhibitors-guideline-from-the-college-of-american-pathologists-the-international-association-for-the-study-of-lung-cancer-and-the-association
#18
Neal I Lindeman, Philip T Cagle, Dara L Aisner, Maria E Arcila, Mary Beth Beasley, Eric Bernicker, Carol Colasacco, Sanja Dacic, Fred R Hirsch, Keith Kerr, David J Kwiatkowski, Marc Ladanyi, Jan A Nowak, Lynette Sholl, Robyn Temple-Smolkin, Benjamin Solomon, Lesley H Souter, Erik Thunnissen, Ming S Tsao, Christina B Ventura, Murry W Wynes, Yasushi Yatabe
CONTEXT: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update...
January 23, 2018: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29396253/updated-molecular-testing-guideline-for-the%C3%A2-selection-of-lung-cancer-patients-for-treatment-with-targeted-tyrosine-kinase-inhibitors-guideline-from-the-college-of-american-pathologists-the%C3%A2-international-association-for-the-study-of-lung-cancer-and-the%C3%A2-association
#19
Neal I Lindeman, Philip T Cagle, Dara L Aisner, Maria E Arcila, Mary Beth Beasley, Eric Bernicker, Carol Colasacco, Sanja Dacic, Fred R Hirsch, Keith Kerr, David J Kwiatkowski, Marc Ladanyi, Jan A Nowak, Lynette Sholl, Robyn Temple-Smolkin, Benjamin Solomon, Lesley H Souter, Erik Thunnissen, Ming S Tsao, Christina B Ventura, Murry W Wynes, Yasushi Yatabe
CONTEXT: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update...
January 23, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29395869/c-raf-ablation-induces-regression-of-advanced-kras-trp53-mutant-lung-adenocarcinomas-by-a-mechanism-independent-of-mapk-signaling
#20
Manuel Sanclemente, Sarah Francoz, Laura Esteban-Burgos, Emilie Bousquet-Mur, Magdolna Djurec, Pedro P Lopez-Casas, Manuel Hidalgo, Carmen Guerra, Matthias Drosten, Monica Musteanu, Mariano Barbacid
A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis...
January 26, 2018: Cancer Cell
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