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Kras lung cancer

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https://www.readbyqxmd.com/read/27936345/targeting-integrin-linked-kinase-to-suppress-oncogenic-kras-signaling-in-pancreatic-cancer
#1
Po-Chen Chu, Samuel K Kulp, Tanios Bekaii-Saab, Ching-Shih Chen
Although oncogenic KRAS represents a therapeutically relevant target in pancreatic cancer, it is deemed "non-druggable" because of the intrinsic difficulty in designing direct inhibitors of KRAS. Our recent work demonstrated a KRAS-integrin-linked kinase (ILK) regulatory feedback loop that allows pancreatic cancer cells to regulate KRAS expression and to interact with the tumor microenvironment to promote aggressive phenotype. KRAS induces E2F1-mediated transcriptional activation of ILK expression, and ILK, in turn, controls KRAS expression via hnRNPA1, which binds and destabilizes the G-quadruplex in the KRAS promoter...
December 9, 2016: Small GTPases
https://www.readbyqxmd.com/read/27924059/an-open-label-phase-ii-study-evaluating-first-line-egfr-tyrosine-kinase-inhibitor-erlotinib-in-non-small-cell-lung-cancer-patients-with-tumors-showing-high-egfr-gene-copy-number
#2
Ewa Szutowicz-Zielińska, Krzysztof Konopa, Anna Kowalczyk, Małgorzata Suszko-Każarnowicz, Renata Duchnowska, Aleksandra Szczęsna, Magdalena Ratajska, Aleksander Sowa, Janusz Limon, Wojciech Biernat, Tomasz Burzykowski, Jacek Jassem, Rafał Dziadziuszko
BACKGROUND: First-line treatment with epidermal growth factor receptor (EGFR) inhibitors in NSCLC is effective in patients with activating EGFR mutations. The activity of erlotinib in patients harboring high EGFR gene copy number has been considered debatable. PATIENTS AND METHODS: A multicenter, open-label, single-arm phase II clinical trial was performed to test the efficacy of erlotinib in the first-line treatment of NSCLC patients harboring high EGFR gene copy number defined as ≥4 copies in ≥40% of cells...
December 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27923066/somatic-genomics-and-clinical-features-of-lung-adenocarcinoma-a-retrospective-study
#3
Jianxin Shi, Xing Hua, Bin Zhu, Sarangan Ravichandran, Mingyi Wang, Cu Nguyen, Seth A Brodie, Alessandro Palleschi, Marco Alloisio, Gianluca Pariscenti, Kristine Jones, Weiyin Zhou, Aaron J Bouk, Joseph Boland, Belynda Hicks, Adam Risch, Hunter Bennett, Brian T Luke, Lei Song, Jubao Duan, Pengyuan Liu, Takashi Kohno, Qingrong Chen, Daoud Meerzaman, Crystal Marconett, Ite Laird-Offringa, Ian Mills, Neil E Caporaso, Mitchell H Gail, Angela C Pesatori, Dario Consonni, Pier Alberto Bertazzi, Stephen J Chanock, Maria Teresa Landi
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression. METHODS AND FINDINGS: We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27922010/mek-inhibitors-block-growth-of-lung-tumours-with-mutations-in-ataxia-telangiectasia-mutated
#4
Michal Smida, Ferran Fece de la Cruz, Claudia Kerzendorfer, Iris Z Uras, Barbara Mair, Abdelghani Mazouzi, Tereza Suchankova, Tomasz Konopka, Amanda M Katz, Keren Paz, Katalin Nagy-Bojarszky, Markus K Muellner, Zsuzsanna Bago-Horvath, Eric B Haura, Joanna I Loizou, Sebastian M B Nijman
Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27912827/new-targets-in-non-small-cell-lung-cancer
#5
REVIEW
Soo J Park, Soham More, Ayesha Murtuza, Brian D Woodward, Hatim Husain
With the implementation of genomic technologies into clinical practice, we have examples of the predictive benefit of targeted therapy for oncogene-addicted cancer and identified molecular dependencies in non-small cell lung cancer. The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy. Advances have validated oncogenic driver genes and led to the development of targeted agents...
February 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/27911940/isoform-specific-effects-of-wild-type-ras-genes-on-carcinogen-induced-lung-tumorigenesis-in-mice
#6
Jamie D Weyandt, John M Carney, Elizabeth N Pavlisko, MengMeng Xu, Christopher M Counter
The gene KRAS is commonly mutated in lung cancer to encode a constitutively active and oncogenic protein that is well established to initiate and maintain lung tumorigenesis. However, the remaining wild-type KRAS protein, or the other family members HRAS and NRAS, can still be activated in the presence of oncogenic KRAS. Moreover, loss of any one of these three genes has been shown to increase the sensitivity of mice to the carcinogen urethane, which induces Kras mutation-positive early lung lesions. To determine the contribution of progressively disrupting Hras and Nras genes on urethane lung tumorigenesis, mice with different combinations of wild-type and null alleles of Hras and Nras were exposed with urethane and tumor burden was assessed...
2016: PloS One
https://www.readbyqxmd.com/read/27911859/kras-exon-2-codon-13-mutation-is-associated-with-a-better-prognosis-than-codon-12-mutation-following-lung-metastasectomy-in-colorectal-cancer
#7
Stéphane Renaud, Francesco Guerrera, Joseph Seitlinger, Lorena Costardi, Mickaël Schaeffer, Benoit Romain, Claudio Mossetti, Anne Claire-Voegeli, Pier Luigi Filosso, Michèle Legrain, Enrico Ruffini, Pierre-Emmanuel Falcoz, Alberto Oliaro, Gilbert Massard
INTRODUCTION: The utilization of molecular markers as routinely used biomarkers is steadily increasing. We aimed to evaluate the potential different prognostic values of KRAS exon 2 codons 12 and 13 after lung metastasectomy in colorectal cancer (CRC). RESULTS: KRAS codon 12 mutations were observed in 116 patients (77%), whereas codon 13 mutations were observed in 34 patients (23%). KRAS codon 13 mutations were associated with both longer time to pulmonary recurrence (TTPR) (median TTPR: 78 months (95% CI: 50...
November 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27906963/lncrna-rmrp-acts-as-an-oncogene-in-lung-cancer
#8
Qingjun Meng, Mingming Ren, Yanguang Li, Xiang Song
Accumulating studies have demonstrated that long noncoding RNAs (lncRNAs) act a crucial role in the development of tumors. However, the role of lncRNAs in lung cancer remains largely unknown. In this study, we demonstrated that theexpression of RMRP was upregulated in lung adenocarcinoma tissues compared to the matched adjacent normal tissues. Moreover, of 35 lung adenocarcinoma samples, RMRP expression was upregulated in 25 cases (25/35; 71.4%) compared to the adjacent normal tissues. We also showed that RMRP expression was upregulated in lung adenocarcinoma cell lines (A549, SPC-A1, H1299 and H23) compared to the bronchial epithelial cell line (16HBE)...
2016: PloS One
https://www.readbyqxmd.com/read/27893707/blockade-of-the-il-6-trans-signalling-stat3-axis-suppresses-cachexia-in-kras-induced-lung-adenocarcinoma
#9
A Miller, L McLeod, S Alhayyani, A Szczepny, D N Watkins, W Chen, P Enriori, W Ferlin, S Ruwanpura, B J Jenkins
Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130(F/F) knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27877053/synergistic-activity-of-vorinostat-combined-with-gefitinib-but-not-with-sorafenib-in-mutant-kras-human-non-small-cell-lung-cancers-and-hepatocarcinoma
#10
Victor Jeannot, Benoit Busser, Laetitia Vanwonterghem, Sophie Michallet, Sana Ferroudj, Murat Cokol, Jean-Luc Coll, Mehmet Ozturk, Amandine Hurbin
Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27876675/a-phase-1-1b-study-evaluating-trametinib-plus-docetaxel-or-pemetrexed-in-patients-with-advanced-non-small-cell-lung-cancer
#11
David R Gandara, Natasha Leighl, Jean-Pierre Delord, Fabrice Barlesi, Jaafar Bennouna, Gerald Zalcman, Jeffrey R Infante, Karen L Reckamp, Karen Kelly, Frances A Shepherd, Julien Mazieres, Filip Janku, Olivia S Gardner, Bijoyesh Mookerjee, Yuehui Wu, Donna S Cox, Dan Schramek, Vijay Peddareddigari, Yuan Liu, Anthony M D'Amelio, George Blumenschein
PURPOSE: This 2-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant non-small cell cancer (NSCLC) cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations...
November 19, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27875625/clinical-and-genetic-determinants-of-ovarian-metastases-from-colorectal-cancer
#12
Karuna Ganesh, Ronak H Shah, Efsevia Vakiani, Garrett M Nash, Hugh P Skottowe, Rona Yaeger, Andrea Cercek, Anne Lincoln, Christina Tran, Neil H Segal, Diane L Reidy, Anna Varghese, Andrew S Epstein, Yukio Sonoda, Dennis Chi, Jose Guillem, Larissa Temple, Philip Paty, Jaclyn Hechtman, Jinru Shia, Martin Weiser, Julio Garcia Aguilar, Nancy Kemeny, Michael F Berger, Leonard Saltz, Zsofia K Stadler
BACKGROUND: Ovarian metastases from colorectal cancer (OM-CRC) often are unresponsive to chemotherapy and are associated with poor survival. To the authors' knowledge, the clinicopathologic and genomic predictors of OM-CRC are poorly characterized and optimal clinical management remains unclear. METHODS: Women with a histopathological diagnosis of OM-CRC who were treated at Memorial Sloan Kettering Cancer Center from 1999 to 2015 were identified. Next-generation somatic mutation profiling (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]) was performed on 38 OM-CRC cases, including 21 matched tumor pairs/trios...
November 22, 2016: Cancer
https://www.readbyqxmd.com/read/27867542/the-expression-of-sall4-is-significantly-associated-with-egfr-but-not-kras-or-eml4-alk-mutations-in-lung-cancer
#13
Xiangbo Jia, Rulin Qian, Binbin Zhang, Song Zhao
BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide; unfortunately, its prognosis is still very poor. Therefore, developing the target molecular is very important for lung cancer diagnosis and treatment, especially in the early stage. With this in view, spalt-like transcription factor 4 (SALL4) is considered a potential biomarker for diagnosis and prognosis in cancers, including lung cancer. METHODS: In order to better investigate the association between the expression of SALL4 and driver genes mutation, 450 histopathologically diagnosed patients with lung cancer and 11 non-cancer patients were enrolled to test the expression of SALL4 and the status of driver genes mutation...
October 2016: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/27863474/hypoxic-resistance-of-kras-mutant-tumor-cells-to-3-bromopyruvate-is-counteracted-by-prima-1-and-reversed-by-n-acetylcysteine
#14
Andrea Orue, Valery Chavez, Mary Strasberg-Rieber, Manuel Rieber
BACKGROUND: The metabolic inhibitor 3-bromopyruvate (3-BrPA) is a promising anti-cancer alkylating agent, shown to inhibit growth of some colorectal carcinoma with KRAS mutation. Recently, we demonstrated increased resistance to 3-BrPA in wt p53 tumor cells compared to those with p53 silencing or mutation. Since hypoxic microenvironments select for tumor cells with diminished therapeutic response, we investigated whether hypoxia unequally increases resistance to 3-BrPA in wt p53 MelJuso melanoma harbouring (Q61L)-mutant NRAS and wt BRAF, C8161 melanoma with (G12D)-mutant KRAS (G464E)-mutant BRAF, and A549 lung carcinoma with a KRAS (G12S)-mutation...
November 18, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27859136/kras-driven-expression-signature-has-prognostic-power-superior-to-mutation-status-in-non-small-cell-lung-cancer
#15
Ádám Nagy, Lőrinc Sándor Pongor, András Szabó, Mariacarmela Santarpia, Balázs Győrffy
KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer. We divided NSCLC patients with mutation and RNA-seq data into KRAS mutated and wild type groups. Mann-Whitney test was used to identify genes showing altered expression between these cohorts...
November 8, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27846317/ras-mitogen-activated-protein-kinase-signal-is-required-for-enhanced-pd-l1-expression-in-human-lung-cancers
#16
Hidetoshi Sumimoto, Atsushi Takano, Koji Teramoto, Yataro Daigo
Ectopic programmed cell death ligand 1 (PD-L1) expression in non-small cell lung cancers (NSCLCs) is related to immune evasion by cancer, and it is a molecular target of immune checkpoint therapies. Although some altered signals in NSCLCs are responsible for ectopic PD-L1 expression, the precise mechanisms remain obscure. Because we found a higher frequency of EGFR/KRAS mutations in NSCLC cell lines with high PD-L1 expression (p < 0.001), we evaluated the relationships between downstream signals and PD-L1 expression, particularly in three KRAS-mutant adenocarcinoma cell lines...
2016: PloS One
https://www.readbyqxmd.com/read/27843638/kras-driven-lung-adenocarcinoma-combined-ddr1-notch-inhibition-as-an-effective-therapy
#17
REVIEW
Chiara Ambrogio, Ernest Nadal, Alberto Villanueva, Gonzalo Gómez-López, Timothy P Cash, Mariano Barbacid, David Santamaría
Understanding the early evolution of cancer heterogeneity during the initial steps of tumorigenesis can uncover vulnerabilities of cancer cells that may be masked at later stages. We describe a comprehensive approach employing gene expression analysis in early lesions to identify novel therapeutic targets and the use of mouse models to test synthetic lethal drug combinations to treat human Kirsten rat sarcoma viral oncogene homologue (KRAS)-driven lung adenocarcinoma.
2016: ESMO Open
https://www.readbyqxmd.com/read/27835880/targeted-depletion-of-pik3r2-induces-regression-of-lung-squamous-cell-carcinoma
#18
Jesús Vallejo-Díaz, Manuel Olazabal-Morán, Ariel E Cariaga-Martínez, María J Pajares, Juana M Flores, Ruben Pio, Luis M Montuenga, Ana C Carrera
Oncogenic mutations in the PI3K/AKT pathway are present in nearly half of human tumors. Nonetheless, inhibitory compounds of the pathway often induce pathway rebound and tumor resistance. We find that lung squamous cell carcinoma (SQCC), which accounts for ~20% of lung cancer, exhibits increased expression of the PI3K subunit PIK3R2, which is at low expression levels in normal tissues. We tested a new approach to interfere with PI3K/AKT pathway activation in lung SQCC. We generated tumor xenografts of SQCC cell lines and examined the consequences of targeting PIK3R2 expression...
November 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27835869/otx015-mk-8628-a-novel-bet-inhibitor-exhibits-antitumor-activity-in-non-small-cell-and-small-cell-lung-cancer-models-harboring-different-oncogenic-mutations
#19
Maria E Riveiro, Lucile Astorgues-Xerri, Ramiro Vazquez, Roberta Frapolli, Ivo Kwee, Andrea Rinaldi, Elodie Odore, Keyvan Rezai, Mohamed Bekradda, Giorgio Inghirami, Maurizio D'Incalci, Kay Noel, Esteban Cvitkovic, Eric Raymond, Francesco Bertoni
Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27829148/pf4-promotes-platelet-production-and-lung-cancer-growth
#20
Ferdinando Pucci, Steffen Rickelt, Andita P Newton, Christopher Garris, Ernesto Nunes, Charles Evavold, Christina Pfirschke, Camilla Engblom, Mari Mino-Kenudson, Richard O Hynes, Ralph Weissleder, Mikael J Pittet
Co-option of host components by solid tumors facilitates cancer progression and can occur in both local tumor microenvironments and remote locations. At present, the signals involved in long-distance communication remain insufficiently understood. Here, we identify platelet factor 4 (PF4, CXCL4) as an endocrine factor whose overexpression in tumors correlates with decreased overall patient survival. Furthermore, engineered PF4 over-production in a Kras-driven lung adenocarcinoma genetic mouse model expanded megakaryopoiesis in bone marrow, augmented platelet accumulation in lungs, and accelerated de novo adenocarcinogenesis...
November 8, 2016: Cell Reports
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