Characteristics of NSCLCs harboring NRAS mutations.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7532-7532
Author(s):  
Kadoaki Ohashi ◽  
Lecia V. Sequist ◽  
Martin Sos ◽  
Xi Chen ◽  
Charles M. Rudin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Cell Lines ◽  
Expression Profiles ◽  
Nsclc Cell ◽  
Disease Stage ◽  
Smoking History ◽  
Egfr Mutations ◽  
Targeted Agents ◽  
Mek Inhibitors

7532 Background: We sought to determine the frequency and clinical characteristics of patients with non-small cell lung cancers (NSCLCs) harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS mutant lung cancer cells. Methods: We reviewed data in the Catalogue of Somatic Mutations in Cancer (COSMIC) and clinical history from patients with NSCLC whose tumors underwent systematic screening for driver mutations including NRAS. Patient characteristics examined included age, gender, race, smoking history, disease stage, treatment history, and overall survival (OS). 6 NSCLC cell lines with NRAS mutations were screened for sensitivity against multiple targeted agents. Gene expression was profiled using Affymetrix U133A arrays in 5 NRAS mutant NSCLC cell lines, 8 with EGFR mutations and 17 with KRAS mutations. Results: Among 4524 patients with NSCLC tested, NRAS mutations were present in 29 (0.64%). The types of substitutions found were Q61H/K/L/R and G12A/C/D/R/S, with NRAS Q61L the most common (n=14; 48%). One tumor had a concurrent KRAS mutation. 83% had adenocarcinoma histology, with no significant differences in gender. While 90% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS than in KRAS-mutant NSCLC (KRAS: 66%, NRAS: 13%, p<0.05). Systemic chemotherapy showed limited efficacy in 7 patients with metastatic disease (median OS 7 mos). 5 of 6 NRAS mutant lung cancer cell lines were sensitive to the MEK inhibitors, AZD6244 and GSK1120212, while other targeted agents (against EGFR, ALK, MET, IGF-1R, PIK3CA, BRAF) were minimally effective. Gene expression profiles of NRAS mutant cell lines were distinct from those with KRAS or EGFR mutations. Conclusions: NRAS mutations define a distinct subset of NSCLCs (~1%) with potential sensitivity to MEK inhibitors. While NRAS gene mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking.

scholarly journals Comprehensive RNA analysis of CSF reveals a role for CEACAM6 in lung cancer leptomeningeal metastases

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Yingmei Li ◽  
Dina Polyak ◽  
Layton Lamsam ◽  
Ian David Connolly ◽  
Eli Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Single Cell ◽  
Cell Lines ◽  
Expression Profiles ◽  
Leptomeningeal Metastases ◽  
Detection Sensitivity ◽  
Nsclc Cell ◽  
Rna Seq ◽  
The Brain

AbstractNon-small cell lung cancer (NSCLC) metastatic to the brain leptomeninges is rapidly fatal, cannot be biopsied, and cancer cells in the cerebrospinal fluid (CSF) are few; therefore, available tissue samples to develop effective treatments are severely limited. This study aimed to converge single-cell RNA-seq and cell-free RNA (cfRNA) analyses to both diagnose NSCLC leptomeningeal metastases (LM), and to use gene expression profiles to understand progression mechanisms of NSCLC in the brain leptomeninges. NSCLC patients with suspected LM underwent withdrawal of CSF via lumbar puncture. Four cytology-positive CSF samples underwent single-cell capture (n = 197 cells) by microfluidic chip. Using robust principal component analyses, NSCLC LM cell gene expression was compared to immune cells. Massively parallel qPCR (9216 simultaneous reactions) on human CSF cfRNA samples compared the relative gene expression of patients with NSCLC LM (n = 14) to non-tumor controls (n = 7). The NSCLC-associated gene, CEACAM6, underwent in vitro validation in NSCLC cell lines for involvement in pathologic behaviors characteristic of LM. NSCLC LM gene expression revealed by single-cell RNA-seq was also reflected in CSF cfRNA of cytology-positive patients. Tumor-associated cfRNA (e.g., CEACAM6, MUC1) was present in NSCLC LM patients’ CSF, but not in controls (CEACAM6 detection sensitivity 88.24% and specificity 100%). Cell migration in NSCLC cell lines was directly proportional to CEACAM6 expression, suggesting a role in disease progression. NSCLC-associated cfRNA is detectable in the CSF of patients with LM, and corresponds to the gene expression profile of NSCLC LM cells. CEACAM6 contributes significantly to NSCLC migration, a hallmark of LM pathophysiology.

scholarly journals Expression Profiles of microRNAs in Drug-Resistant Non-Small Cell Lung Cancer Cell Lines Using microRNA Sequencing

2018 ◽  
Vol 51 (6) ◽  
pp. 2509-2522 ◽  
Author(s):  
Shousen Hu ◽  
Yongliang Yuan ◽  
Zhizhen Song ◽  
Dan Yan ◽  
Xiangzhen Kong
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Expression Profiles ◽  
Small Cell ◽  
Nsclc Cell ◽  
Drug Resistant ◽  
Small Cell Lung

Background/Aims: Drug resistance remains a main obstacle to the treatment of non- small cell lung cancer (NSCLC). The aim of this study was to identify the expression profiles of microRNAs (miRNAs) in drug-resistant NSCLC cell lines. Methods: The expression profiles of miRNAs in drug-resistant NSCLC cell lines were examined using miRNA sequencing, and the common dysregulated miRNAs in these cell lines were identified and analyzed by bioinformatics methods. Results: A total of 29 upregulated miRNAs and 36 downregulated miRNAs were found in the drug-resistant NSCLC cell lines, of which 26 upregulated and 36 downregulated miRNAs were found to be involved in the Ras signaling pathway. The expression levels, survival analysis, and receiver operating characteristic curve of the dysregulated miRNAs based on The Cancer Genome Atlas database for lung adenocarcinoma showed that hsa-mir-192, hsa-mir-1293, hsa-mir-194, hsa-mir-561, hsa-mir-205, hsa-mir-30a, and hsa-mir-30c were related to lung cancer, whereas only hsa-mir-1293 and hsa-mir-561 were not involved in drug resistance. Conclusion: The results of this study may provide novel biomarkers for drug resistance in NSCLC and potential therapies for overcoming drug resistance, and may also reveal the potential mechanisms underlying drug resistance in this disease.

scholarly journals Computational identification of biomarker genes for lung cancer considering treatment and non-treatment studies

2020 ◽  
Vol 21 (S9) ◽  
Author(s):  
Mona Maharjan ◽  
Raihanul Bari Tanvir ◽  
Kamal Chowdhury ◽  
Wenrui Duan ◽  
Ananda Mohan Mondal
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cancer Cell Lines ◽  
High Expression ◽  
Different Types ◽  
Low Expression

Abstract Background Lung cancer is the number one cancer killer in the world with more than 142,670 deaths estimated in the United States alone in the year 2019. Consequently, there is an overreaching need to identify the key biomarkers for lung cancer. The aim of this study is to computationally identify biomarker genes for lung cancer that can aid in its diagnosis and treatment. The gene expression profiles of two different types of studies, namely non-treatment and treatment, are considered for discovering biomarker genes. In non-treatment studies healthy samples are control and cancer samples are cases. Whereas, in treatment studies, controls are cancer cell lines without treatment and cases are cancer cell lines with treatment. Results The Differentially Expressed Genes (DEGs) for lung cancer were isolated from Gene Expression Omnibus (GEO) database using R software tool GEO2R. A total of 407 DEGs (254 upregulated and 153 downregulated) from non-treatment studies and 547 DEGs (133 upregulated and 414 downregulated) from treatment studies were isolated. Two Cytoscape apps, namely, CytoHubba and MCODE, were used for identifying biomarker genes from functional networks developed using DEG genes. This study discovered two distinct sets of biomarker genes – one from non-treatment studies and the other from treatment studies, each set containing 16 genes. Survival analysis results show that most non-treatment biomarker genes have prognostic capability by indicating low-expression groups have higher chance of survival compare to high-expression groups. Whereas, most treatment biomarkers have prognostic capability by indicating high-expression groups have higher chance of survival compare to low-expression groups. Conclusion A computational framework is developed to identify biomarker genes for lung cancer using gene expression profiles. Two different types of studies – non-treatment and treatment – are considered for experiment. Most of the biomarker genes from non-treatment studies are part of mitosis and play vital role in DNA repair and cell-cycle regulation. Whereas, most of the biomarker genes from treatment studies are associated to ubiquitination and cellular response to stress. This study discovered a list of biomarkers, which would help experimental scientists to design a lab experiment for further exploration of detail dynamics of lung cancer development.

O-76 Oligonucleotide microarray gene expression profiles of lung cancer cell lines sensitive and resistant to ZD-1839

Lung Cancer ◽  
2003 ◽  
Vol 41 ◽  
pp. S25
Author(s):  
Wilbur A. Franklin ◽  
Barbara A. Helfrich ◽  
Michio Sugita ◽  
Razvan Lapadat ◽  
Fred R. Hirsch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cancer Cell Lines ◽  
Lung Cancer Cell ◽  
Microarray Gene Expression ◽  
Microarray Gene

scholarly journals Cancer cell-intrinsic expression of MHC II in lung cancer cell lines is actively restricted by MEK/ERK signaling and epigenetic mechanisms

2020 ◽  
Vol 8 (1) ◽  
pp. e000441 ◽  
Author(s):  
Alexander J Neuwelt ◽  
Abigail K Kimball ◽  
Amber M Johnson ◽  
Benjamin W Arnold ◽  
Bonnie L Bullock ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Nsclc Cell ◽  
Erk Signaling ◽  
Mhc I ◽  
Mek Inhibitors ◽  
Mhc Ii ◽  
Programmed Death ◽  
Mitogen Activated Protein

BackgroundProgrammed death 1/programmed death ligand 1 (PD-1/PD-L1) targeted immunotherapy affords clinical benefit in ~20% of unselected patients with lung cancer. The factor(s) that determine whether a tumor responds or fails to respond to immunotherapy remains an active area of investigation. We have previously defined divergent responsiveness of two KRAS-mutant cell lines to PD-1/PD-L1 blockade using an orthotopic, immunocompetent mouse model. Responsiveness to PD-1/PD-L1 checkpoint blockade correlates with an interferon gamma (IFNγ)-inducible gene signature and major histocompatibility complex class II (MHC II) expression by cancer cells. In the current study, we aim to identify therapeutic targets that can be manipulated in order to enhance cancer-cell-specific MHC II expression.MethodsResponsiveness to IFNγ and induction of MHC II expression was assessed after various treatment conditions in mouse and human non-small cell lung cancer (NSCLC) cell lines using mass cytometric and flow cytometric analysis.ResultsSingle-cell analysis using mass and flow cytometry demonstrated that IFNγ consistently induced PD-L1 and MHC class I (MHC I) across multiple murine and human NSCLC cell lines. In contrast, MHC II showed highly variable induction following IFNγ treatment both between lines and within lines. In mouse models of NSCLC, MHC II induction was inversely correlated with basal levels of phosphorylated extracellular signal-regulated kinase (ERK) 1/2, suggesting potential mitogen-activated protein (MAP) kinase-dependent antagonism of MHC II expression. To test this, cell lines were subjected to varying levels of stimulation with IFNγ, and assessed for MHC II expression in the presence or absence of mitogen-activated protein kinase kinase (MEK) inhibitors. IFNγ treatment in the presence of MEK inhibitors significantly enhanced MHC II induction across multiple lung cancer lines, with minimal impact on expression of either PD-L1 or MHC I. Inhibition of histone deacetylases (HDACs) also enhanced MHC II expression to a more modest extent. Combined MEK and HDAC inhibition led to greater MHC II expression than either treatment alone.ConclusionsThese studies emphasize the active inhibitory role that epigenetic and ERK signaling cascades have in restricting cancer cell-intrinsic MHC II expression in NSCLC, and suggest that combinatorial blockade of these pathways may engender new responsiveness to checkpoint therapies.

scholarly journals Elevated phosphorylation of EGFR in NSCLC due to mutations in PTPRH

2021 ◽  
Author(s):  
Matthew R Swiatnicki ◽  
Jonathan P Rennhack ◽  
Daniel Hollern ◽  
Ashlee V Perry ◽  
Rachel Kubiak ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Mouse Model ◽  
Tyrosine Kinase ◽  
Expression Profiles ◽  
Nsclc Cell ◽  
Egfr Mutations ◽  
Nsclc Cell Line ◽  
Parental Line

The role of EGFR in lung cancer is well described with numerous activating mutations that result in phosphorylation and tyrosine kinase inhibitors that target EGFR. While the role of the EGFR kinase in non-small cell lung cancer (NSCLC) is appreciated, control of EGFR signaling pathways through dephosphorylation by phosphatases is not as clear. In recent work we identified mutations in Protein Tyrosine Phosphatase Receptor Type H (Ptprh, also known as SAP-1) as being associated with elevated phosphorylation of EGFR in a mouse model of breast cancer. We have examined a series of tumors from this mouse model, revealing conserved V483M Ptprh mutations within the FVB background, but a series of varied mutations in other backgrounds. Despite the varied Ptprh mutations in other background strains, matched primary and metastatic tumors largely shared mutational profiles. Profiling the downstream events of Ptprh mutant tumors revealed AKT activation, suggesting a key target of PTPRH was EGFR tyrosine 1197. Given the role of EGFR in lung cancer, we explored TCGA data which revealed that a subset of PTPRH mutant tumors shared gene expression profiles with EGFR mutant tumors, but that EGFR mutations and PTPRH mutations were mutually exclusive. Generation of a PTPRH knockout NSCLC cell line resulted in Y1197 phosphorylation of EGFR, and a rescue with expression of wild type PTPRH returned EGFR phosphorylation to parental line values while a rescue with a D986A catalytically dead mutant PTPRH did not, demonstrating that PTPRH targets EGFR. As expected with active EGFR, the knockout of PTPRH was associated with increased growth rate. Moreover, a dose response curve illustrated that two human NSCLC lines that had naturally occurring PTPRH mutations responded to EGFR tyrosine kinase inhibition. Injection of one of the NSCLC human lines into mice resulted in tumors, and Osimertinib treatment resulted in a reduction of tumor volume relative to vehicle controls. Consistent with prior literature from breast cancer, PTPRH mutation resulted in nuclear pEGFR as seen in immunohistochemistry, suggesting that there may also be a role for EGFR as a transcriptional co-factor. Other roles for PTPRH were explored through a receptor tyrosine kinase array, noting elevated phosphorylation of FGFR1. Knockout of PTPRH in NSCLC cell lines resulted in elevated phosphorylated FGFR1 relative to controls, indicating that PTPRH has a number of targets that may be aberrantly activated in NSCLC with mutations in PTPRH. Together these data suggest that mutations in PTPRH in NSCLC may result in clinically actionable alterations using existing therapies.

The Key microRNAs Regulated the Development of Non-small Cell Lung Cancer by Targeting TGF-β-induced epithelial–mesenchymal Transition

2019 ◽  
Vol 22 (4) ◽  
pp. 238-244 ◽  
Author(s):  
Gang Chen ◽  
Bo Ye
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Normal Lung ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Mesenchymal Transition

Purpose: Epithelial-to-Mesenchymal Transition (EMT) was reported to play a key role in the development of Non-Small Cell Lung Cancer (NSCLC). The process of EMT is regulated by the changes of miRNAs expression. However, it is still unknown which miRNA changed the most in the process of canceration and whether these changes played a role in tumor development. Methods: A total of 36 SCLC patients treated in our hospital between 11th, 2015 and 10th, 2017 were enrolled. The samples of cancer tissues and paracancer tissues of patients were collected and analyzed. Then, the miRNAs in normal lung cells and NSCLC cells were also analyzed. In the presence of TGF-β, we transfected the miRNA mimics or inhibitor into NSCLC cells to investigate the role of the significantly altered miRNAs in cell migration and invasion and in the process of EMT. Results: MiR-330-3p was significantly up-regulated in NSCLC cell lines and tissues and miRNA- 205 was significantly down-regulated in NSCLC cell lines and NSCLC tissues. Transfected miRNA-205 mimics or miRMA-330-3p inhibitor inhibited the migration and invasion of NCIH1975 cell and restrained TGF-β-induced EMT in NSCLC cells. Conclusion: miRNA-330-3p and miRNA-205 changed the most in the process of canceration in NSCLC. Furthermore, miR-330-3p promoted cell invasion and metastasis in NSCLC probably by promoting EMT and miR-205 could restrain NSCLC likely by suppressing EMT.

scholarly journals Nicotine promotes the development of non-small cell lung cancer through activating LINC00460 and PI3K/Akt signaling

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Hongying Zhao ◽  
Yu Wang ◽  
Xiubao Ren
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Akt Signaling ◽  
Small Cell ◽  
Nsclc Cell ◽  
Expression Level ◽  
In Vitro Experiments ◽  
Small Cell Lung

Abstract Objective: Nicotine, the main ingredient in tobacco, is identified to facilitate tumorigenesis and accelerate metastasis in tumor. Studies in recent years have reported that long intergenic non-protein coding RNA 460 (LINC00460) is strongly associated with lung cancer poor prognosis and nicotine dependence. Nonetheless, it is unclear whether nicotine promotes the development of lung cancer through activation of LINC00460. Methods: We determined that LINC00460 expression in lung cancer tissues and the prognosis in patients with non-small cell lung carcinoma (NSCLC) using Gene Expression Profiling Interactive Analysis (GEPIA) website and The Cancer Genome Atlas (TCGA) database. Through in vitro experiments, we studied the effects of nicotine on LINC00460 in NSCLC cells lines using Cell Counting Kit-8 (CCK-8), transwell test, flow cytometry, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot assays. Results: We identified the significant up-regulated expression level of LINC00460 in NSCLC tissues and cell lines, especially, the negative correlation of LINC00460 expression level with overall survival (OS). In in vitro experiments, LINC00460 was overexpressed in NSCLC cell lines under nicotine stimulation. Nicotine could relieve the effect of LINC00460 knockdown on NSCLC cell proliferation, migration and apoptosis. The same influence was observed on PI3K/Akt signaling pathway. Conclusions: In summary, this is the first time to examine the potential roles of LINC00460 in lung cancer cell proliferation, migration and apoptosis induced by nicotine. This may help to develop novel therapeutic strategies for the prevention and treatment of metastatic tumors from cigarette smoke-caused lung cancer by blocking the nicotine-activated LINC00460 pathway.

scholarly journals Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Kaili Long ◽  
Lili Gu ◽  
Lulu Li ◽  
Ziyu Zhang ◽  
Enjie Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Small Molecule ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Molecular Compound ◽  
Small Cell Lung

AbstractApurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

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