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.
Highlights
Nuclear erythroid related factor-2 (NRF2) is a leucine zipper transcription factor and the master regulator of the antioxidant response (AR) pathway
This led us to hypothesize that inhibition of NRF2 function and concomitant cellular accumulation of reactive oxygen species (ROS) are possible mechanistic components and basis of action of HER2targeted immunotherapy
We demonstrate that combination treatment with HER2 targeting monoclonal antibodies, Pertuzumab and Trastuzumab, causes inhibition of NRF2 function and subsequent repression of NRF2 dependent antioxidant response pathway in human ovarian cancer cell lines
Summary
Nuclear erythroid related factor-2 (NRF2) is a leucine zipper transcription factor and the master regulator of the antioxidant response (AR) pathway It drives both basal and oxidative stress-induced transcription of a battery of phase I, II, and III detoxification enzymes and cytoprotective genes [1,2,3], as well as other genes of the metabolic and signal transduction pathways [2,3,4]. Following oxidative stress or in the presence of NRF2 activators, a number of cysteine residues within KEAP1 become oxidized causing conformational changes in the KEAP1 structure This disables KEAP1 to bind additional NRF2 and cause its degradation leading to nuclear accumulation www.impactjournals.com/oncotarget of NRF2, activation of its transcriptional function to induce transactivation of ARE-containing genes and restoration of cellular redox homeostasis [8]
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