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https://www.readbyqxmd.com/read/28647837/targeting-metabolic-reprogramming-in-kras-driven-cancers
#1
REVIEW
Kenji Kawada, Kosuke Toda, Yoshiharu Sakai
Mutations of KRAS are found in a variety of human malignancies, including in pancreatic cancer, colorectal cancer, and non-small cell lung cancer at high frequency. To date, no effective treatments that target mutant variants of KRAS have been introduced into clinical practice. In recent years, a number of studies have shown that the oncogene KRAS plays a critical role in controlling cancer metabolism by orchestrating multiple metabolic changes. One of the metabolic hallmarks of malignant tumor cells is their dependency on aerobic glycolysis, known as the Warburg effect...
June 24, 2017: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28647672/therapeutic-targeting-of-nuclear-export-inhibition-in-lung-cancer
#2
Arjun Gupta, Jessica M Saltarski, Michael A White, Pier P Scaglioni, David E Gerber
Intracellular compartmentalization and trafficking of molecules plays a critical role in complex and essential cellular processes. In lung cancer and other malignancies, aberrant nucleocytoplasmic transport of tumor suppressor proteins and cell cycle regulators results in tumorigenesis and inactivation of apoptosis. Pharmacologic targeting of this process, termed selective inhibition of nuclear export (SINE), has demonstrated anti-tumor efficacy in preclinical models and human clinical trials. Exportin-1 (XPO1)-which serves as the sole exporter of several tumor suppressor proteins and cell cycle regulators, including retinoblastoma (Rb), adenomatous polyposis coli (APC), p53, p73, p21, p27, FOXO, STAT3, IKB, topoisomerase II and PAR-4-is the principal focus of SINE drug development...
June 21, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28647671/use-of-oncogenic-driver-mutations-in-staging-of-multiple-primary-lung-carcinomas-a-single-center-experience
#3
Ramsey Asmar, Joshua R Sonett, Gopal Singh, Mahesh M Mansukhani, Alain C Borczuk
PURPOSE: The staging of multiple pulmonary adenocarcinomas requires the distinction of intrapulmonary metastasis (IPM) from multiple primary lung cancers (MPLC). This can be challenging in some patients, and the addition of data from oncogenic driver mutations in these tumors may be helpful in this determination. PROCEDURES: As a proof of principle, molecular driver results from primary tumors and their metastases in 45 patients were compared (cohort 1). Then, 69 patients with a total of 154 synchronous or metachronous lung carcinomas were identified, with pathologic findings compared to oncogenic driver mutation...
June 21, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28642450/cbp501-inhibits-egf-dependent-cell-migration-invasion-and-epithelial-to-mesenchymal-transition-of-non-small-cell-lung-cancer-cells-by-blocking-kras-to-calmodulin-binding
#4
Naoya Saito, Naoki Mine, Donald W Kufe, Daniel D Von Hoff, Takumi Kawabe
The anti-cancer agent CBP501 binds to calmodulin (CaM). Recent studies showed that migration and metastasis are inhibited by several CaM antagonists. However, there is no available evidence that CBP501 has similar effects. Here we found that CBP501 inhibits migration of non-small cell lung cancer (NSCLC) cells in vitro, even in the presence of migration inducing factors such as WNT, IL-6, and several growth factors. CBP501 also inhibited epidermal growth factor (EGF) enhanced invasion and the epithelial-to-mesenchymal transition (EMT), and this inhibition was accompanied by (i) suppression of Akt and ERK1/2 phosphorylation, and (ii) suppression of expression of transcription factor Zeb1 and the mesenchymal marker Vimentin...
June 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28639239/significant-improvement-in-detecting-braf-kras-and-egfr-mutations-using-next-generation-sequencing-as-compared-with-fda-cleared-kits
#5
Wanlong Ma, Steven Brodie, Sally Agersborg, Vincent A Funari, Maher Albitar
INTRODUCTION: We compared mutations detected in EGFR, KRAS, and BRAF genes using next-generation sequencing (NGS) and confirmed by Sanger sequencing with mutations that could be detected by FDA-cleared testing kits. METHODS: Paraffin-embedded tissue from 822 patients was tested for mutations in EGFR, KRAS, and BRAF by NGS. Sanger sequencing of hot spots was used with locked nucleic acid to increase sensitivity for specific hot-spot mutations. This included 442 (54%) lung cancers, 168 (20%) colorectal cancers, 29 (4%) brain tumors, 33 (4%) melanomas, 14 (2%) thyroid cancers, and 16% others (pancreas, head and neck, and cancer of unknown origin)...
June 21, 2017: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/28637019/clinicopathological-characteristics-of-ros1-and-ret-rearranged-nsclc-in-caucasian-patients-data-from-a-cohort-of-713-non-squamous-nsclc-lacking-kras-egfr-her2-braf-pik3ca-alk-alterations
#6
Frédéric Dugay, Francisco Llamas-Gutierrez, Marjory Gournay, Sarah Medane, François Mazet, Dan Christian Chiforeanu, Emmanuelle Becker, Régine Lamy, Hervé Léna, Nathalie Rioux-Leclercq, Marc-Antoine Belaud-Rotureau, Florian Cabillic
Targeted therapies have substantially changed the management of non-small cell lung cancer (NSCLC) patients with driver oncogenes. Given the high frequency, EGFR and ALK aberrations were the first to be detected and paved the way for tyrosine kinase inhibitor (TKI) treatments. Other kinases such as ROS1 and more recently RET have emerged as promising targets, and ROS1 and RET TKIs are already available for precision medicine.We screened a large cohort of 713 Caucasian non-squamous NSCLC patients lacking EGFR/KRAS/BRAF/HER2/PI3KCA/ALK aberrations for ROS1 and RET rearrangements using fluorescence in situ hybridization to determine the frequency and clinicopathological characteristics of ROS1- and RET-positive patients...
June 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636540/implementation-and-utilization-of-the-molecular-tumor-board-to-guide-precision-medicine
#7
REVIEW
Shuko Harada, Rebecca Arend, Qian Dai, Jessica A Levesque, Thomas S Winokur, Rongjun Guo, Martin J Heslin, Lisle Nabell, L Burt Nabors, Nita A Limdi, Kevin A Roth, Edward E Partridge, Gene P Siegal, Eddy S Yang
BACKGROUND: With rapid advances in genomic medicine, the complexity of delivering precision medicine to oncology patients across a university health system demanded the creation of a Molecular Tumor Board (MTB) for patient selection and assessment of treatment options. The objective of this report is to analyze our progress to date and discuss the importance of the MTB in the implementation of personalized medicine. MATERIALS AND METHODS: Patients were reviewed in the MTB for appropriateness for comprehensive next generation sequencing (NGS) cancer gene set testing based on set criteria that were in place...
June 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28634206/papers-of-note-in-science-translational-medicine9-394
#8
Leslie K Ferrarelli
This week's articles describe how broccoli can combat type 2 diabetes, how monocytes contribute to the failure of organ transplant grafts, and how to more durably treat RET- or KRAS-driven lung cancer.
June 20, 2017: Science Signaling
https://www.readbyqxmd.com/read/28633480/a-prospective-examination-of-circulating-tumor-cell-profiles-in-non-small-cell-lung-cancer-molecular-subgroups
#9
C R Lindsay, V Faugeroux, S Michiels, E Pailler, F Facchinetti, D Ou, M V Bluthgen, C Pannet, M Ngo-Camus, G Bescher, C Caramella, F Billiot, J Remon, D Planchard, J-C Soria, B Besse, F Farace
Background: We report the first study examining the clinical, numerical and biological properties of circulating tumor cells (CTCs) according to molecular subtypes of non-small cell lung cancer (NSCLC). Patients and Methods: 125 patients with treatment-naïve stage IIIb-IV NSCLC were prospectively recruited for CellSearch analysis. Anti-vimentin antibody was included for examination of CTCs to assess their mesenchymal character. Associations of total CTCs and vimentin-positive (vim +) CTCs with clinical characteristics, tumor genotype and survival were assessed...
June 19, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28631135/long-term-clinical-benefit-from-salvage-egfr-tyrosine-kinase-inhibitors-in-advanced-non-small-cell-lung-cancer-patients-with-egfr-wild-type-tumors
#10
F Koinis, A Voutsina, A Kalikaki, A Koutsopoulos, E Lagoudaki, E Tsakalaki, E K Dermitzaki, E Kontopodis, A G Pallis, V Georgoulias, A Kotsakis
BACKGROUND: Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond. PATIENTS AND METHODS: Patients with EGFRwt NSCLC who received salvage (≥2nd line) treatment with erlotinib for a prolonged period (>6 months), were sought from the database of the Hellenic Oncology Research Group...
June 19, 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/28625654/line-1-hypomethylation-is-associated-to-specific-clinico-pathological-features-in-stage-i-non-small-cell-lung-cancer
#11
Andrea Imperatori, Nora Sahnane, Nicola Rotolo, Francesca Franzi, Elisa Nardecchia, Laura Libera, Chiara Romualdi, Maria Cattoni, Fausto Sessa, Lorenzo Dominioni, Daniela Furlan
OBJECTIVES: We hypothesize that selected genetic and/or epigenetic changes associated with advanced tumours may help identifying early non-small cell lung cancers (NSCLCs) that recur after resection. Among epigenetic changes, long interspersed nuclear element-1 (LINE-1) hypomethylation is seen early during carcinogenesis and may act in concert with genetic alterations to cancer progression. LINE-1 hypomethylation and gene mutations frequently involved in lung cancer, were analysed to evaluate their prognostic role in resected stage I NSCLC...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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
#12
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/28620690/acquired-resistance-to-erlotinib-in-egfr-mutation-positive-lung-adenocarcinoma-among-hispanics-clicap
#13
Andrés F Cardona, Oscar Arrieta, Martín Ignacio Zapata, Leonardo Rojas, Beatriz Wills, Noemí Reguart, Niki Karachaliou, Hernán Carranza, Carlos Vargas, Jorge Otero, Pilar Archila, Claudio Martín, Luis Corrales, Mauricio Cuello, Carlos Ortiz, Luis E Pino, Rafael Rosell, Zyanya Lucia Zatarain-Barrón
BACKGROUND: Lung cancer harboring epidermal growth factor receptor (EGFR) mutations and treated with EGFR tyrosine kinase inhibitors (TKIs) all eventually develop acquired resistance to the treatment, with half of the patients developing EGFR T790M resistance mutations. OBJECTIVE: The purpose of this study was to assess histological and clinical characteristics and survival outcomes in Hispanic EGFR mutated lung cancer patients after disease progression. PATIENTS AND METHODS: EGFR mutation-positive lung cancer patients (n = 34) with acquired resistance to the EGFR-TKI erlotinib were identified from 2011 to 2015...
June 15, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28619094/morphologic-and-molecular-study-of-lung-cancers-associated-with-idiopathic-pulmonary-fibrosis-and-other-pulmonary-fibroses
#14
Alice Guyard, Claire Danel, Nathalie Théou-Anton, Marie-Pierre Debray, Laure Gibault, Pierre Mordant, Yves Castier, Bruno Crestani, Gérard Zalcman, Hélène Blons, Aurélie Cazes
BACKGROUND: Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). METHODS: Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group...
June 15, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28616588/all-for-one-and-fosl1-for-all-fosl1-at-the-crossroads-of-lung-and-pancreatic-cancer-driven-by-mutant-kras
#15
Adrian Vallejo, Karmele Valencia, Silvestre Vicent
KRAS proto-oncogene, GTPase (KRAS) remains refractory to current therapies. We devised an integrative cross-tumor approach to expose common core elements up-regulated in mutant KRAS cancers that could provide new treatment opportunities. This approach identified FOSL1 (Fos-like antigen 1) as a clinically and functionally relevant gene in mutant KRAS-driven lung and pancreatic cancers, and unveiled downstream transcriptional targets amenable to pharmacological inhibition.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28615361/targeting-kras-dependent-tumors-with-azd4785-a-high-affinity-therapeutic-antisense-oligonucleotide-inhibitor-of-kras
#16
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/28614784/erlotinib-based-doublet-targeted-therapy-versus-erlotinib-alone-in-previously-treated-advanced-non-small-cell-lung-cancer-a-meta-analysis-from-24-randomized-controlled-trials
#17
REVIEW
Jian-Wei Gao, Ping Zhan, Xiang-Yu Qiu, Jia-Jia Jin, Tang-Feng Lv, Yong Song
BACKGROUND: To assess the efficacy profile of erlotinib-based doublet targeted therapy compared with erlotinib monotherapy for previously treated patients with advanced NSCLC, a meta-analysis was performed. PATIENTS AND METHODS: We rigorously searched PubMed, Embase, Cochrane and meeting proceedings. Phase II/III randomized trials reporting on the efficacy of erlotinib-doublet therapy versus single-agent therapy were selected. We estimated the HR for OS, PFS and the RR for ORR, DCR, 1-year SR...
May 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28609226/phase-ii-trial-of-atezolizumab-as-first-line-or-subsequent-therapy-for-patients-with-programmed-death-ligand-1-selected-advanced-non-small-cell-lung-cancer-birch
#18
Solange Peters, Scott Gettinger, Melissa L Johnson, Pasi A Jänne, Marina C Garassino, Daniel Christoph, Chee Keong Toh, Naiyer A Rizvi, Jamie E Chaft, Enric Carcereny Costa, Jyoti D Patel, Laura Q M Chow, Marianna Koczywas, Cheryl Ho, Martin Früh, Michel van den Heuvel, Jeffrey Rothenstein, Martin Reck, Luis Paz-Ares, Frances A Shepherd, Takayasu Kurata, Zhengrong Li, Jiaheng Qiu, Marcin Kowanetz, Simonetta Mocci, Geetha Shankar, Alan Sandler, Enriqueta Felip
Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1-expressing cells, respectively]) were enrolled...
June 13, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28608966/next-generation-sequencing-and-clinical-outcomes-of-patients-with-lung-adenocarcinoma-treated-with-stereotactic-body-radiotherapy
#19
Richard J Cassidy, Xinyan Zhang, Pretesh R Patel, Joseph W Shelton, Chase E Escott, Gabriel L Sica, Michael R Rossi, Charles E Hill, Conor E Steuer, Rathi N Pillai, Suresh S Ramalingam, Taofeek K Owonikoko, Madhusmita Behera, Seth D Force, Felix G Fernandez, Walter J Curran, Kristin A Higgins
BACKGROUND: Genetic aberrations are well characterized in lung adenocarcinomas (LACs) and clinical outcomes have been influenced by targeted therapies in the advanced setting. Stereotactic body radiotherapy (SBRT) is the standard-of-care therapy for patients with nonoperable, early-stage LAC, but to the authors' knowledge, no information is available regarding the impact of genomic changes in these patients. The current study sought to determine the frequency and clinical impact of genetic aberrations in this population...
June 13, 2017: Cancer
https://www.readbyqxmd.com/read/28601386/detection-of-alk-and-kras-mutations-in-circulating-tumor-dna-of-patients-with-advanced-alk-positive-nsclc-with-disease-progression-during-crizotinib-treatment
#20
Paola Bordi, Marcello Tiseo, Eleonora Rofi, Iacopo Petrini, Giuliana Restante, Romano Danesi, Marzia Del Re
BACKGROUND: In patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), disease progression occurs after a median of 9 to 10 months of crizotinib treatment. Several mechanisms of resistance have been identified and include ALK mutations and amplification or the activation of bypassing signaling pathways. Rebiopsy in NSCLC patients represents a critical issue and the analysis of circulating cell-free DNA (cfDNA) has a promising role for the identification of resistance mechanisms...
May 18, 2017: Clinical Lung Cancer
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