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https://www.readbyqxmd.com/read/29911108/emerging-application-of-genomics-guided-therapeutics-in-personalized-lung-cancer-treatment
#1
REVIEW
Aubhishek Zaman, Trever G Bivona
In lung cancer, genomics-driven comprehensive molecular profiling has identified novel chemically and immunologically addressable vulnerabilities, resulting in an increasing application of precision medicine by targeted inactivation of tumor oncogenes and immunogenic activation of host anti-tumor surveillance as modes of treatment. However, initially profound response of these targeted therapies is followed by relapse due to therapy-resistant residual disease states. Although distinct mechanisms and frameworks for therapy resistance have been proposed, accounting for and upfront prediction of resistance trajectories has been challenging...
May 2018: Annals of Translational Medicine
https://www.readbyqxmd.com/read/29909489/ets1-regulates-twist1-transcription-in-a-kras-g12d-lkb1-metastatic-lung-tumor-model-of-non-small-cell-lung-cancer
#2
Guetchyn Millien, Yuxia Cao, Carl J O'Hara, Jean-Bosco Tagne, Anne Hinds, Mary C Williams, Maria I Ramirez, Hasmeena Kathuria
Distinct members of the Ets family of transcription factors act as positive or negative regulators of genes involved in cellular proliferation, development, and tumorigenesis. In human lung cancer, increased ETS1 expression is associated with poor prognosis and metastasis. We tested whether ETS1 contributes to lung tumorigenesis by binding to Twist1, a gene involved in tumor cell motility and dissemination. We used a mouse lung cancer model with metastasis driven by conditionally activated Kras and concurrent tumor suppressor Lkb1 loss (Kras G12D / Lkb1-/- model) and a similar model of lung cancer that does not metastasize, driven by conditionally activated Kras alone (Kras G12D model)...
June 16, 2018: Clinical & Experimental Metastasis
https://www.readbyqxmd.com/read/29906786/ct-features-of-her2-mutant-lung-adenocarcinomas
#3
REVIEW
Peter Sawan, Andrew J Plodkowski, Angela E Li, Bob T Li, Alexander Drilon, Marinela Capanu, Michelle S Ginsberg
OBJECTIVES: To describe the radiological phenotype of HER2-mutant lung cancers on CT at presentation. METHODS: Eligible patients with lung adenocarcinomas with HER2 mutations were stage-matched with two control groups (EGFR- and KRAS-mutant groups). Evaluated CT features of the primary tumor included size, location, consistency, contour, presence of pleural tags and pleural retractions. Presence of pleural effusions, lung metastases, adenopathy, chest wall invasion, and were also recorded...
June 7, 2018: Clinical Imaging
https://www.readbyqxmd.com/read/29906244/de-novo-lipogenesis-represents-a-therapeutic-target-in-mutant-kras-non-small-cell-lung-cancer
#4
Anju Singh, Christian Ruiz, Kavita Bhalla, John A Haley, Qing Kay Li, George Acquaah-Mensah, Emily Montal, Kuladeep R Sudini, Ferdinandos Skoulidis, Ignacio I Wistuba, Vassiliki Papadimitrakopoulou, John V Heymach, Laszlo G Boros, Edward Gabrielson, Julian Carretero, Kwok-Kin Wong, John D Haley, Shyam Biswal, Geoffrey D Girnun
Oncogenic Kras mutations are one of the most common alterations in non-small cell lung cancer and are associated with poor response to treatment and reduced survival. Driver oncogenes, such as Kras are now appreciated for their ability to promote tumor growth via up-regulation of anabolic pathways. Therefore, we wanted to identify metabolic vulnerabilities in Kras-mutant lung cancer. Using the Kras LSL-G12D lung cancer model, we show that mutant Kras drives a lipogenic gene-expression program. Stable-isotope analysis reveals that mutant Kras promotes de novo fatty acid synthesis in vitro and in vivo...
June 15, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29899852/concomitant-driver-mutations-in-advanced-egfr-mutated-non-small-cell-lung-cancer-and-their-impact-on-erlotinib-treatment
#5
Jan Nyrop Jakobsen, Eric Santoni-Rugiu, Morten Grauslund, Linea Melchior, Jens Benn Sørensen
Background: Patients with EGFR -mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes. Methods: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR -mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET -amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR -mutated tumor samples from erlotinib-treated patients...
May 25, 2018: Oncotarget
https://www.readbyqxmd.com/read/29894909/kras-reasons-for-optimism-in-lung-cancer
#6
REVIEW
C R Lindsay, M Jamal-Hanjani, M Forster, F Blackhall
Despite being the most frequent gain-of-function genetic alteration in human cancer, KRAS mutation has to date offered only limited potential as a prognostic and predictive biomarker. Results from the phase III SELECT-1 trial in non-small cell lung cancer (NSCLC) recently added to a number of historical and more contemporary disappointments in targeting KRAS mutant disease, including farnesyl transferase inhibition and synthetic lethality partners such as STK33. This narrative review uses the context of these previous failures to demonstrate how the knowledge gained from these experiences can be used as a platform for exciting advances in NSCLC on the horizon...
June 9, 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29892061/mutations-in-the-swi-snf-complex-induce-a-targetable-dependence-on-oxidative-phosphorylation-in-lung-cancer
#7
Yonathan Lissanu Deribe, Yuting Sun, Christopher Terranova, Fatima Khan, Juan Martinez-Ledesma, Jason Gay, Guang Gao, Robert A Mullinax, Tin Khor, Ningping Feng, Yu-Hsi Lin, Chia-Chin Wu, Claudia Reyes, Qian Peng, Frederick Robinson, Akira Inoue, Veena Kochat, Chang-Gong Liu, John M Asara, Cesar Moran, Florian Muller, Jing Wang, Bingliang Fang, Vali Papadimitrakopoulou, Ignacio I Wistuba, Kunal Rai, Joseph Marszalek, P Andrew Futreal
Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium...
June 8, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29872579/adenoviral-vectors-transduce-alveolar-macrophages-in-lung-cancer-models
#8
Darinee D Tippimanchai, Kyle Nolan, Joanna Poczobutt, Gregory Verzosa, Howard Li, Hannah Scarborough, Jing Huang, Christian Young, James DeGregori, Raphael A Nemenoff, Stephen P Malkoski
Adenoviral vectors expressing Cre recombinase are commonly used to initiate tumor formation in murine lung cancer models. While these vectors are designed to target genetic recombination to lung epithelial cells, adenoviruses can infect additional cell types that potentially influence tumor development. Our goal was to explore the consequences of adenoviral-mediated alveolar macrophage (AM) transduction in a Kras-initiated lung tumor model. As expected, treatment of animals harboring the KrasLSL-G12D allele and an inducible green fluorescence protein (GFP) tracking allele with an adenoviral vector expressing Cre recombinase under the control of the cytomegalovirus (CMV) promoter (Ad5-CMV-Cre), caused GFP-positive lung adenocarcinomas...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29862231/beyond-egfr-and-alk-targeting-rare-mutations-in-advanced-non-small-cell-lung-cancer
#9
REVIEW
Stavros Gkolfinopoulos, Giannis Mountzios
Lung cancer remains the leading cause of cancer-related death in men and women, despite its constantly declining rates in incidence and mortality in the developed world. The past decade has witnessed an unprecedented rise in the development of molecular targeted therapies in various types of tumors. In non-small cell lung cancer (NSCLC), the greatest paradigm shift is the implementation of EGFR and ALK tyrosine kinase inhibitors in the first line and subsequent lines of therapy, with impressive results. Though less frequent than the molecular alterations in the aforementioned genes, a number of aberrations in potential oncogenic drivers has been discovered, namely mutations in the genes KRAS , BRAF , HER2 , PI3KCA and DDR2 , ROS1 and RET rearrangements and MET , HER2 and FGFR1 gene amplifications...
April 2018: Annals of Translational Medicine
https://www.readbyqxmd.com/read/29858031/association-of-molecular-status-and-metastatic-organs-at-diagnosis-in-patients-with-stage-iv-non-squamous-non-small-cell-lung-cancer
#10
C C H J Kuijpers, L E L Hendriks, J L Derks, A-M C Dingemans, A S R van Lindert, M M van den Heuvel, R A Damhuis, S M Willems
OBJECTIVES: Biological predisposition for specific metastatic organs might differ between molecular subgroups of lung cancer. We aimed to assess the association between molecular status and metastatic organs at diagnosis in a nationwide stage IV non-squamous non-small cell lung cancer ((ns)-NSCLC) cohort. METHODS: All ns-NSCLC from 2013 that were stage IV at diagnosis were identified from the Netherlands Cancer Registry, which records information on metastatic organs at diagnosis...
July 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29808009/mutant-kras-driven-cancers-depend-on-ptpn11-shp2-phosphatase
#11
Dietrich A Ruess, Guus J Heynen, Katrin J Ciecielski, Jiaoyu Ai, Alexandra Berninger, Derya Kabacaoglu, Kivanc Görgülü, Zahra Dantes, Sonja M Wörmann, Kalliope N Diakopoulos, Angeliki F Karpathaki, Marlena Kowalska, Ezgi Kaya-Aksoy, Liang Song, Eveline A Zeeuw van der Laan, María P López-Alberca, Marc Nazaré, Maximilian Reichert, Dieter Saur, Mert M Erkan, Ulrich T Hopt, Bruno Sainz, Walter Birchmeier, Roland M Schmid, Marina Lesina, Hana Algül
The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors 1 . Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways1-7 . Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro 8 ...
May 28, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29808006/shp2-is-required-for-growth-of-kras-mutant-non-small-cell-lung-cancer-in-vivo
#12
Sara Mainardi, Antonio Mulero-Sánchez, Anirudh Prahallad, Giovanni Germano, Astrid Bosma, Paul Krimpenfort, Cor Lieftink, Jeffrey D Steinberg, Niels de Wit, Samuel Gonçalves-Ribeiro, Ernest Nadal, Alberto Bardelli, Alberto Villanueva, Rene Bernards
RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3 . Inhibition of the RAS oncoproteins has proven difficult 4 , and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms 8 . It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10 ...
May 28, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29797762/a-combined-tissue-engineered-in-silico-signature-tool-for-patient-stratification-in-lung-cancer
#13
Claudia Göttlich, Meik Kunz, Cornelia Zapp, Sarah L Nietzer, Heike Walles, Thomas Dandekar, Gudrun Dandekar
Patient-tailored therapy based on tumor drivers is promising for lung cancer treatment. For this we combined in vitro tissue models with in silico analyses. Using individual cell lines with specific mutations we demonstrate a generic and rapid stratification pipeline for targeted tumor therapy. We improve in vitro models of tissue-conditions by a biological matrix-based three-dimensional (3D) tissue culture that allows in vitro drug testing: it correctly shows a strong drug response upon gefitinib treatment in a cell line harboring an EGFR activating mutation (HCC827), but no clear drug response upon treatment with the HSP90 inhibitor 17AAG in two cell lines with KRAS mutations (H441, A549)...
May 24, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29795377/an-anti-egfr-%C3%A3-cotinine-bispecific-antibody-complexed-with-cotinine-conjugated-duocarmycin-inhibits-growth-of-egfr-positive-cancer-cells-with-kras-mutations
#14
Junyeong Jin, Gunwoo Park, Jong Bae Park, Soohyun Kim, Hyori Kim, Junho Chung
Antibody-drug conjugates (ADCs) can selectively deliver cytotoxic agents to tumor cells and are frequently more potent than naked antibodies. However, optimization of the conjugation process between antibodies and cytotoxic agents and characterization of ADCs are laborious and time-consuming processes. Here, we describe a novel ADC platform using a tetravalent bispecific antibody that simultaneously binds to the tumor-associated antigen and a hapten conjugated to a cytotoxic agent. We selected cotinine as the hapten because it is not present in biological systems and is inert and nontoxic...
May 24, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29788737/diagnosis-for-carcinoma-of-unknown-primary-site-with-the-aid-of-simple-pcr-tests-a-single-center-experience
#15
E Suspitsin, G Yanus, E Imyanitov
This study was aimed to incorporate PCR testing in the determination of organ/tissue origin for cancers of unknown primary site (CUP). We developed a PCR panel consisting of 7 expression markers (CDX2, CDH17, SPB, UGRP, MAM, LPB, TG) and 2 genes frequently mutated in cancer (KRAS and BRAF). The expression tests were intentionally interpreted in a non-quantitative way, i.e. classified tumors either as positive or negative expressors. While applying these tests to 135 cancers belonging to 8 common types of adenocarcinomas (AdCa), we observed that this panel was capable to clearly discriminate between gastrointestinal vs...
March 14, 2018: Neoplasma
https://www.readbyqxmd.com/read/29787863/validity-of-targeted-next-generation-sequencing-in-routine-care-for-identifying-clinically-relevant-molecular-profiles-in-non-small-cell-lung-cancer-results-of-a-2-year-experience-on-1-343-samples
#16
Antoine Legras, Marc Barritault, Anne Tallet, Elizabeth Fabre, Alice Guyard, Bastien Rance, William Digan, Nicolas Pecuchet, Etienne Giroux-Leprieur, Catherine Julie, Stéphane Jouveshomme, Véronique Duchatelle, Véronique Giraudet, Laure Gibault, Alain Cazier, Jean Pastre, Françoise LE Pimpec-Barthes, Pierre Laurent-Puig, Hélène Blons
Theranostic assays are based on single gene testing but the ability of next-generation sequencing (NGS) to interrogate numerous genetic alterations will progressively replace single gene assays. Although NGS was evaluated to screen for theranostic mutations, its usefulness in clinical practice on large series of samples remains to be demonstrated. NGS performance was assessed following guidelines. TaqMan probes and NGS were compared for their ability to detect EGFR and KRAS mutations and NGS mutation profiles were analyzed on a large series of NSCLC (n=1,343)...
May 19, 2018: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29781848/anatomical-resections-improve-survival-following-lung-metastasectomy-of-colorectal-cancer-harboring-kras-mutations
#17
Stéphane Renaud, Joseph Seitlinger, Yaseen Al Lawati, Francesco Guerrera, Pierre-Emmanuel Falcoz, Gilbert Massard, Lorenzo Ferri, Jonathan Spicer
OBJECTIVE: The aim of this study was to evaluate the benefit of anatomical resection (AR) in lung metastasectomy (LM) of colorectal cancer (CRC) harboring KRAS mutations SUMMARY BACKGROUND DATA:: KRAS mutations are related to high aggressiveness in the lung metastasis of CRC. It is unknown whether AR can lead to better outcomes than can non-AR (NAR) in KRAS patients. METHODS: We retrospectively reviewed the data from 574 consecutive patients who underwent a LM for CRC...
May 17, 2018: Annals of Surgery
https://www.readbyqxmd.com/read/29772692/insurance-coverage-policies-for-pharmacogenomic-and-multi-gene-testing-for-cancer
#18
Christine Y Lu, Stephanie Loomer, Rachel Ceccarelli, Kathleen M Mazor, James Sabin, Ellen Wright Clayton, Geoffrey S Ginsburg, Ann Chen Wu
Insurance coverage policies are a major determinant of patient access to genomic tests. The objective of this study was to examine differences in coverage policies for guideline-recommended pharmacogenomic tests that inform cancer treatment. We analyzed coverage policies from eight Medicare contractors and 10 private payers for 23 biomarkers (e.g., HER2 and EGFR ) and multi-gene tests. We extracted policy coverage and criteria, prior authorization requirements, and an evidence basis for coverage. We reviewed professional society guidelines and their recommendations for use of pharmacogenomic tests...
May 16, 2018: Journal of Personalized Medicine
https://www.readbyqxmd.com/read/29765524/cross-platform-comparison-for-the-detection-of-ras-mutations-in-cfdna-ddpcr-biorad-detection-assay-beaming-assay-and-ngs-strategy
#19
Jessica Garcia, Julien Forestier, Eric Dusserre, Anne-Sophie Wozny, Florence Geiguer, Patrick Merle, Claire Tissot, Carole Ferraro-Peyret, Frederick S Jones, Daniel L Edelstein, Valérie Cheynet, Claire Bardel, Gaelle Vilchez, Zhenyu Xu, Pierre Paul Bringuier, Marc Barritault, Karen Brengle-Pesce, Marielle Guillet, Marion Chauvenet, Brigitte Manship, Marie Brevet, Claire Rodriguez-Lafrasse, Valérie Hervieu, Sébastien Couraud, Thomas Walter, Léa Payen
CfDNA samples from colon (mCRC) and non-small cell lung cancers (NSCLC) (CIRCAN cohort) were compared using three platforms: droplet digital PCR (ddPCR, Biorad); BEAMing/OncoBEAM™-RAS-CRC (Sysmex Inostics); next-generation sequencing (NGS, Illumina), utilizing the 56G oncology panel (Swift Biosciences). Tissue biopsy and time matched cfDNA samples were collected at diagnosis in the mCRC cohort and during 1st progression in the NSCLC cohort. Excellent matches between cfDNA/FFPE mutation profiles were observed...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29764856/-tp53-stk11-and-egfr-mutations-predict-tumor-immune-profile-and-the-response-to-anti-pd-1-in-lung-adenocarcinoma
#20
Jerome Biton, Audrey Mansuet-Lupo, Nicolas Pécuchet, Marco Alifano, Hanane Ouakrim, Jennifer Arrondeau, Pascaline Boudou-Rouquette, Francois Goldwasser, Karen Leroy, Jeremy Goc, Marie Wislez, Claire Germain, Pierre Laurent-Puig, Marie-Caroline Dieu-Nosjean, Isabelle Cremer, Ronald Herbst, Hélène F Blons, Diane Damotte
PURPOSE: By unlocking anti-tumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed. EXPERIMENTAL DESIGN: We performed in depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry and transcriptomic data...
May 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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