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      Comprehensive analysis of circular RNA profiling in AZD9291‐resistant non‐small cell lung cancer cell lines

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          Abstract

          Background

          Osimertinib (AZD9291), a third‐generation EGFR‐tyrosine kinase inhibitor, can effectively prolong survival in non‐small cell lung cancer (NSCLC) patients with EGFR mutations, particularly T790M mutations; however, acquired resistance to AZD9291 is inevitable, thus exploration of the targets of resistance is urgent.

          Methods

          Considering the important role of circular RNAs (circRNAs) in cancers, we established AZD9291‐resistant NSCLC cell lines (H1975/AZDR and HCC827/AZDR) and used microarray analysis to determine the circRNA expression profiles of the cells. The H1975/AZDR and HCC827/AZDR cell lines were induced by gradually increasing the drug concentration. CircRNA microarray expression profiles were obtained from H1975, HCC827, H1975/AZDR, and HCC827/AZDR cells and validated by quantitative reverse transcription PCR. Expression data were analyzed bioinformatically.

          Results

          The H1975/AZDR and HCC827/AZDR cell lines were successfully established. The half‐maximal inhibitory concentration and the invasion ability of H1975/AZDR and HCC827/AZDR cells were significantly enhanced. The proliferation rates of H1975/AZDR and HCC827/AZDR were much lower than H1975 and HCC827. Microarray analysis identified 15 504 circRNAs differentially expressed in H1975, HCC827, H1975/AZDR, and HCC827/AZDR cells. Among them, 7966 were upregulated and 7538 were downregulated more than two‐fold. We predicted the possible miRNAs of the top dysregulated circRNAs. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the most modulated circRNAs regulate several cancers and cancer‐related pathways.

          Conclusion

          Our results reveal that circRNAs may play a role in NSCLC AZD9291 resistance and might be a promising molecular target candidate for gene therapy.

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          Most cited references 28

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          Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.

          All patients with EGF receptor (EGFR)-mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted. Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2. Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%-70%] and four had small cell transformation (3%, 95% CI, 0%-6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%-13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%-32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%-4%). Overlap among mechanisms of acquired resistance was seen in 4%. This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs.
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            Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents.

            Efforts to discover new cancer drugs and predict their clinical activity are limited by the fact that laboratory models to test drug efficacy do not faithfully recapitulate this complex disease. One important model system for evaluating candidate anticancer agents is human tumour-derived cell lines. Although cultured cancer cells can exhibit distinct properties compared with their naturally growing counterparts, recent technologies that facilitate the parallel analysis of large panels of such lines, together with genomic technologies that define their genetic constitution, have revitalized efforts to use cancer cell lines to assess the clinical utility of new investigational cancer drugs and to discover predictive biomarkers.
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              Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance.

              Although in vitro models have been a cornerstone of anti-cancer drug development, their direct applicability to clinical cancer research has been uncertain. Using a state-of-the-art Taqman-based quantitative RT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of six cancer types, in established cancer cell lines (grown in monolayer, 3D scaffold, or in xenograft) and clinical samples, either containing >75% tumor cells or microdissected. The MDR transcriptome was determined a priori based on an extensive curation of the literature published during the last three decades, which led to the enumeration of 380 genes. No correlation was found between clinical samples and established cancer cell lines. As expected, we found up-regulation of genes that would facilitate survival across all cultured cancer cell lines evaluated. More troubling, however, were data showing that all of the cell lines, grown either in vitro or in vivo, bear more resemblance to each other, regardless of the tissue of origin, than to the clinical samples they are supposed to model. Although cultured cells can be used to study many aspects of cancer biology and response of cells to drugs, this study emphasizes the necessity for new in vitro cancer models and the use of primary tumor models in which gene expression can be manipulated and small molecules tested in a setting that more closely mimics the in vivo cancer microenvironment so as to avoid radical changes in gene expression profiles brought on by extended periods of cell culture.
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                Author and article information

                Contributors
                docyyh@163.com
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                18 March 2019
                April 2019
                : 10
                : 4 ( doiID: 10.1111/tca.2019.10.issue-4 )
                : 930-941
                Affiliations
                [ 1 ] Shanghai Lung Cancer Center, Shanghai Chest Hospital Shanghai Jiao Tong University Shanghai China
                [ 2 ] School of Pharmaceutical Sciences Wenzhou Medical University Zhejiang China
                [ 3 ] Department of Thoracic Surgery, Shanghai Chest Hospital Shanghai Jiao Tong University Shanghai China
                [ 4 ] Department of Radiation Oncology, Shanghai Cancer Center Fudan University Shanghai China
                Author notes
                [* ] Correspondence

                Yunhai Yang, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huaihai West Road, Shanghai 200030, China.

                Tel: +86 21 2220 0278

                Fax: +86 21 6280 1109

                Email: docyyh@ 123456163.com

                [†]

                Tianxiang Chen, Jizhuang Luo, and Yu Gu contributed equally to this work.

                Article
                TCA13032
                10.1111/1759-7714.13032
                6449233
                30883029
                © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 8, Tables: 2, Pages: 12, Words: 6720
                Product
                Funding
                Funded by: Department of Health of Zhejiang Provincial Government
                Award ID: 2013KYA070
                Funded by: National Natural Science Foundation of China
                Award ID: 81601995
                Award ID: 81301996
                Funded by: Nurture projects for basic research of Shanghai Chest Hospital
                Award ID: 2018YNJCM04
                Funded by: Open Fund of Zhejiang Provincial Top Key Discipline of Pharmacology
                Award ID: YKFJ2‐001
                Funded by: Science and Technology Commission of Shanghai Municipality
                Award ID: 18411966100
                Funded by: Wu Jieping Medical Foundation
                Award ID: 320.6750.17525
                Funded by: Zhejiang Provincial Natural Science Foundation of China
                Award ID: LY16H160022
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                tca13032
                April 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:04.04.2019

                azd9291, circular rna, microarray, nsclc, resistance

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