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    Development and characterisation of a panel of phosphatidylinositide 3-kinase – mammalian target of rapamycin inhibitor resistant lung cancer cell lines


    Heavey, Susan and Dowling, Paul and Moore, Gillian and Barr, Martin P and Kelly, Niamh and Maher, Stephen G and Cuffe, Sinead and Finn, Stephen P and O'Byrne, Kenneth J. and Gately, Kathy (2018) Development and characterisation of a panel of phosphatidylinositide 3-kinase – mammalian target of rapamycin inhibitor resistant lung cancer cell lines. Scientific Reports, 8 (1652). ISSN 2045-2322

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    Abstract

    The PI3K-mTOR pathway is involved in regulating all hallmarks of cancer, and is often dysregulated in NSCLC, making it an attractive therapeutic target in this setting. Acquired resistance to PI3K-mTOR inhibition is a major hurdle to overcome in the success of PI3K-mTOR targeted agents. H460, A549, and H1975 resistant cells were generated by prolonged treatment in culture with Apitolisib (GDC-0980), a dual PI3K-mTOR inhibitor over a period of several months, from age-matched parent cells. Resistance was deemed to have developed when a log fold diference in IC50 had been achieved. Resistant cell lines also exhibited resistance to another widely investigated PI3K-mTOR dual inhibitor; Dactolisib (BEZ235). Cell lines were characterised at the level of mRNA (expression array profling expression of >150 genes), miRNA (expression array profling of 2100 miRNAs), protein (bottoms-up label-free mass spectrometry) and phosphoprotein (expression array profling of 84 phospho/total proteins). Key alterations were validated by qPCR and Western blot. H1975 cells were initially most sensitive to Apitolisib (GDC-0980), but developed resistance more quickly than the other cell lines, perhaps due to increased selective pressure from the impressive initial efect. In-depth molecular profling suggested epithelial-mesenchymal transition (EMT) may play a role in resistance to PI3K-mTOR dual inhibition in NSCLC.

    Item Type: Article
    Additional Information: The authors would like to thank the Irish Cancer Society for funding this work, grant code CRS11HEA. © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
    Keywords: Development; characterisation; phosphatidylinositide; 3-kinase; mammalian; target; rapamycin inhibitor; resistant; lung cancer; cell lines;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 13098
    Identification Number: https://doi.org/10.1038/s41598-018-19688-1
    Depositing User: Paul Dowling
    Date Deposited: 23 Jun 2020 15:33
    Journal or Publication Title: Scientific Reports
    Publisher: Nature Publishing Group
    Refereed: Yes
    Funders: Irish Cancer Society
    URI:

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