Analysis of lncRNA, miRNA and mRNA-associated ceRNA networks and identification of potential drug targets for drug-resistant non-small cell lung cancer

Lung cancer is one of the most important health risks worldwide for human. Non-small cell lung cancer (NSCLC) is the most common cause of premature death from malignant disease. This study provides in-depth insights from systems biology analyses to identify molecular to inform systemic drug targeting in NSCLC. Gene expression profiles from non small cell lung cancer were analyzed with genome-scale biomolecular networks (I,e., protein-protein interaction, transcriptional and post transcriptional regulatory networks). The aim of the study was to determine the pathways and expression profile of the genes to discover molecular signature at RNA and protein levels which could serve as potential drug targets for therapeutics innovation and the identification of novel targets. Eight proteins, six TFs and seven miRNAs came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq. Risk discrimination performance of the reporter biomolecules NPR3, JUN, PPARG, TP53, CKMT1A, SP3 and TFAP2A were also evaluated. Total 213 drugs and 7 proteins were found for non small cell lung cancer through dgidb. Among these identified drugs seven drugs such as- Gemcitabine, Carboplatin, paclitaxel, Docetaxel, Crizotinib, Bevacizumab and Gemcitabine is used for NSCLC which is approved by National Cancer Institute. The molecular signatures and repurposed drugs presented here permit further attention for experimental studies which are offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of NSCLC.

Download Full-text

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

Cellular Physiology and Biochemistry ◽

10.1159/000495921 ◽

2018 ◽

Vol 51 (6) ◽

pp. 2509-2522 ◽

Cited By ~ 9

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.

Download Full-text

Discovery of Nonquinone Substrates for NAD(P)H: Quinone Oxidoreductase 1 (NQO1) as Effective Intracellular ROS Generators for the Treatment of Drug-Resistant Non-Small-Cell Lung Cancer

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.8b01424 ◽

2018 ◽

Vol 61 (24) ◽

pp. 11280-11297 ◽

Cited By ~ 6

Author(s):

Xingsen Wu ◽

Xiang Li ◽

Zhihong Li ◽

Yancheng Yu ◽

Qidong You ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Drug Resistant ◽

Small Cell Lung ◽

Quinone Oxidoreductase ◽

Intracellular Ros

Download Full-text

Rearranged During Transfection Fusions in Non-Small Cell Lung Cancer

Cancers ◽

10.3390/cancers11050620 ◽

2019 ◽

Vol 11 (5) ◽

pp. 620 ◽

Cited By ~ 2

Author(s):

Connor O’Leary ◽

Wen Xu ◽

Nick Pavlakis ◽

Derek Richard ◽

Ken O’Byrne

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Drug Targets ◽

Kinase Inhibitors ◽

Therapeutic Option ◽

Response Rates ◽

Small Cell ◽

Small Cell Lung ◽

Asian Ethnicity

Identifying and targeting specific oncogenic drivers has become standard of care in the routine management of patients with lung cancer. Research is ongoing to expand the number of drug targets that can offer clinically meaningful outcomes. Rearranged during transfection (RET) fusions are the latest oncogenic driver alterations that show potential as a drug target. RET fusions occur in 1–2% of non-small cell lung cancer (NSCLC) cases. They are more commonly associated with younger age, female gender, non-smokers and Asian ethnicity. The RET kinase is abnormally activated through fusion with a partner protein such as KIF5B, CCDC6 or NCOA4. This leads to downstream intracellular signalling and enhancement of gene transcription and cell proliferation. The effectiveness of multi-kinase inhibitors in RET positive NSCLC has been explored in early phase and retrospective studies. From these studies, the most effective agents identified include cabozantanib and vandetanib. Overall response rates (ORR) vary from 18–47% across studies. In general, these agents have a manageable toxicity profile, although there are a number of off-target toxicities. Similar to the increased activity in ALK rearranged disease, pemetrexed has demonstrated superior response rates in this patient group and should be considered. Selective RET inhibitors, including LOXO-292 and BLU-667, are progressing in clinical trials. LOXO-292 has demonstrated an impressive ORR of 77% in RET positive solid tumours. It is anticipated this agent will be an effective targeted therapeutic option for patients with RET positive lung cancer.

Download Full-text

Antitumor effect of Chinese herb oridonin on human non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13526 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13526-e13526

Author(s):

Siyu Chen ◽

Wei Tian ◽

Ai-Hong Ma ◽

Sonal Desai ◽

Krysteena Tolentino ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Antitumor Effect ◽

Chinese Herb ◽

Small Cell ◽

Nsclc Cell ◽

Potential Drug ◽

Small Cell Lung

e13526 Background: Oridonin, a diterpenoid purified from the Chinese herb Rabdosia rubescens, has anti-inflammatory and potentially anti-tumor property. We aimed to study the antitumor effect of oridonin on a panel of human non-small cell lung cancer (NSCLC) cell lines. Methods: Human NSCLC cell lines with a wild-type EGFR gene and a RAS gene mutation were treated with escalating dose concentration of oridonin (from 2.5 to 50 µM). Antitumor effect was measured by 72-hr growth inhibition by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell morphology was observed under microscope. Ongoing experiments will identify potential drug target(s) by assessing changes in global gene expression. Results: Oridonin exhibited a dose-dependent and time-dependent cytotoxic effect on a panel of NSCLC cell lines. Table 1 summarizes the molecular and histological features of these NSCLC cells, and their cytotoxicity to oridinin, erlotinib and pemetrexed. In those NSCLC cells that were sensitive to oridonin, morphological changes were consistent with autophagy and apoptosis. Potential drug targets will be verified by RT-PCR and immunoblotting. Conclusions: Oridonin exerts a distinct cytotoxicity that is independent of the sensitivity of NSCLC cells to erlotinib or pemetrexed. Further mechanistic and animal studies are warranted to understand its anti-tumor property and toxicity profile in preclinical evaluation. [Table: see text]

Download Full-text