A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

• Published in: Oncotarget Vol. 7; no. 46; pp. 75874 - 75901
• Main Authors: Khalil, Hilal S, Langdon, Simon P, Goltsov, Alexey, Soininen, Tero, Harrison, David J, Bown, James, Deeni, Yusuf Y
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 15.11.2016
• Subjects: Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Biomarkers; Cell Line, Tumor; Cell Proliferation - drug effects; Computational Biology - methods; CpG Islands; DNA Methylation; Drug Synergism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Gene Regulatory Networks; Glutathione - metabolism; Histone Deacetylases - metabolism; Humans; Immunotherapy; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Phosphorylation; Promoter Regions, Genetic; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Reactive Oxygen Species - metabolism; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Research Paper; Signal Transduction - drug effects; Pertuzumab/Trastuzumab; HER2-targeted; NRF2; cancer-immunotherapeutics; ROS
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.12425

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.