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dc.contributor.authorKhalil, Hilal S.
dc.contributor.authorLangdon, Simon P.
dc.contributor.authorGoltsov, Alexey
dc.contributor.authorSoininen, Tero
dc.contributor.authorHarrison, David James
dc.contributor.authorBrown, James
dc.contributor.authorDeeni, Yusuf Y.
dc.identifier.citationKhalil , H S , Langdon , S P , Goltsov , A , Soininen , T , Harrison , D J , Brown , J & Deeni , Y Y 2016 , ' A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells ' , Oncotarget , vol. 7 , no. 46 , pp. 75874-75901 .
dc.identifier.otherPURE: 246403193
dc.identifier.otherPURE UUID: aa14c4eb-28f9-457d-979f-0cb93af7ff8a
dc.identifier.otherScopus: 84996720563
dc.identifier.otherWOS: 000389632800113
dc.identifier.otherORCID: /0000-0001-9041-9988/work/64034252
dc.descriptionThis work was supported by grants from The Northwood Trust, Breakthrough Breast Cancer and Scottish Funding Council (SRDG), and personal support to AG from Scottish Informatics and Computer Science Alliance (SICSA).en
dc.description.abstractNuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptoractivation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2drugs, Trastuzumab and Pertuzumab, involving NRF2.HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reductionin NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single antibody alone;downregulated NRF2 substrates by repressing the Antioxidant Response (AR)pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination ofTrastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target.
dc.rightsCopyright 2016 the Author(s). Licensed under a Creative Commons Attribution 3.0 License.en
dc.subjectRC0254 Neoplasms. Tumors. Oncology (including Cancer)en
dc.subjectQA75 Electronic computers. Computer scienceen
dc.subjectQH301 Biologyen
dc.titleA novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cellsen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.description.statusPeer revieweden

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