title: A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells.
abstract: Nuclear 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 receptor activation 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-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2.HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in 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 of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target.
authors.affiliation: Division of Science, School of Science, Engineering and Technology, Abertay University, Dundee, DD1 1HG, United Kingdom.
authors.forename: Hilal S
authors.initials: HS
authors.lastname: Khalil
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
authors.affiliation: Division of Science, School of Science, Engineering and Technology, Abertay University, Dundee, DD1 1HG, United Kingdom.
authors.forename: Alexey
authors.initials: A
authors.lastname: Goltsov
authors.affiliation: Division of Science, School of Science, Engineering and Technology, Abertay University, Dundee, DD1 1HG, United Kingdom.
authors.forename: Tero
authors.initials: T
authors.lastname: Soininen
authors.affiliation: School of Medicine, University of St Andrews, St Andrews, KY16 9TF, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.affiliation: Division of Computing and Mathematics, School of Arts, Media, and Computer Games, Abertay University, Dundee, DD1 1HG, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Bown
authors.affiliation: Division of Science, School of Science, Engineering and Technology, Abertay University, Dundee, DD1 1HG, United Kingdom.
authors.forename: Yusuf Y
authors.initials: YY
authors.lastname: Deeni
mesh_terms: D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D018899:CpG Islands; D019175:DNA Methylation; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks; D005978:Glutathione / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D005978:Glutathione; D006655:Histone Deacetylases; D051267:NF-E2-Related Factor 2; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; C495635:NFE2L2 protein, human
keywords: HER2-targeted; NRF2; Pertuzumab/Trastuzumab; ROS; cancer-immunotherapeutics