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    PP2A inhibition overcomes acquired resistance to HER2 targeted therapy


    McDermott, Martina S.J. and Browne, Brigid C. and Conlon, Neil T. and O'Brien, Neil A. and Slamon, Dennis J. and Henry, Michael and Meleady, Paula and Clynes, Martin and Dowling, Paul and Crown, John and O'Donovan, Norma (2014) PP2A inhibition overcomes acquired resistance to HER2 targeted therapy. Molecular Cancer, 13 (157). pp. 1-12. ISSN 1476-4598

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    Abstract

    Background: HER2 targeted therapies including trastuzumab and more recently lapatinib have significantly improved the prognosis for HER2 positive breast cancer patients. However, resistance to these agents is a significant clinical problem. Although several mechanisms have been proposed for resistance to trastuzumab, the mechanisms of lapatinib resistance remain largely unknown. In this study we generated new models of acquired resistance to HER2 targeted therapy and investigated mechanisms of resistance using phospho-proteomic profiling. Results: Long-term continuous exposure of SKBR3 cells to low dose lapatinib established a cell line, SKBR3-L, which is resistant to both lapatinib and trastuzumab. Phospho-proteomic profiling and immunoblotting revealed significant alterations in phospho-proteins involved in key signaling pathways and molecular events. In particular, phosphorylation of eukaryotic elongation factor 2 (eEF2), which inactivates eEF2, was significantly decreased in SKBR3-L cells compared to the parental SKBR3 cells. SKBR3-L cells exhibited significantly increased activity of protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates eEF2. SKBR3-L cells showed increased sensitivity to PP2A inhibition, with okadaic acid, compared to SKBR3 cells. PP2A inhibition significantly enhanced response to lapatinib in both the SKBR3 and SKBR3-L cells. Furthermore, treatment of SKBR3 parental cells with the PP2A activator, FTY720, decreased sensitivity to lapatinib. The alteration in eEF2 phosphorylation, PP2A activity and sensitivity to okadaic acid were also observed in a second HER2 positive cell line model of acquired lapatinib resistance, HCC1954-L. Conclusions: Our data suggests that decreased eEF2 phosphorylation, mediated by increased PP2A activity, contributes to resistance to HER2 inhibition and may provide novel targets for therapeutic intervention in HER2 positive breast cancer which is resistant to HER2 targeted therapies.

    Item Type: Article
    Additional Information: © 2014 McDermott et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. This work was supported by the Irish Research Council for Science Engineering and Technology (post-graduate fellowship), the Health Research Board (CSA/2007/11), Science Foundation Ireland (08/SRC/B1410), the Cancer Clinical Research Trust, the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT Grant (CCRC13GAL) and SFI and EACR travel fellowships.
    Keywords: HER2; lapatinib; Resistance; eEF2; PP2A;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 5635
    Identification Number: https://doi.org/10.1186/1476-4598-13-157
    Depositing User: Paul Dowling
    Date Deposited: 18 Dec 2014 15:12
    Journal or Publication Title: Molecular Cancer
    Publisher: BioMed Central
    Refereed: Yes
    Funders: Irish Research Council for Science Engineering and Technology, Health Research Board, Science Foundation Ireland, Cancer Clinical Research Trust, Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT Grant, Science Foundation Ireland, European Association for Cancer Research: EACR
    URI:

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