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.

Mechanisms Underlying the Action and Synergism of Trastuzumab and Pertuzumab in Targeting HER2-Positive Breast Cancer

“…Moreover, pertuzumab can abrogate the inhibitory effect of HER2 on the degradation of HER3 [ 174 ]. A recent study showed that both trastuzumab and pertuzumab inhibit NRF2 function in ovarian cancers and the combination of the antibodies produces more potent effects than a single antibody alone [ 175 ]. In summary, while the data regarding the mode of action of pertuzumab is quite limited, the available data mostly support the role of pertuzumab in blocking the heterodimerization of HER2, which in turn blocks the activation of HER2- and HER3-mediated signal transduction pathways leading to cancer cell proliferation and survival.…”

Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies

“…In turn, this suggests that Heme oxygenase inhibitors could represent a potential therapeutic strategy. Following the findings of the role of NRF2 in chemoresistance, researchers have focussed on identifying NRF2 inhibitors to modulate NRF2 to overcome chemoresistance [51,55,[80][81][82][83][84][85][86][87][88][89][90][91][92][93][94] .…”

“…In anticancer chemotherapy, NRF2 and NRF-dependent genes have been implicated in the cellular resistance to a wide range of anticancer agents (e.g., tamoxifen, Cisplatin, Oxaliplatin, Cisplatin, Doxorubicin, and Etoposide) and cancer types [18][19][20][21][22][23][24][25] . Likewise, the NRF2-centred system and signalling pathway is shown to modulate the action and effectiveness of certain receptor targeted therapies [26][27][28]224,231,232] and potentially promoting cancer resistance to such interventions as Trastuzumab, Pertuzumab, Erlotinib, Lapatinib, imatinib, Gefitinib, Afatinib and Osimertinib. In both anticancer chemotherapy and receptor target therapy, the inhibition of NRF2 and its function seemingly and contextually enhanced drug sensitisation of cancers and/or helped to overcome drug resistance.…”

NRF2 Regulates HER1 Signaling Pathway to Modulate the Sensitivity of Ovarian Cancer Cells to Lapatinib and Erlotinib

“…This was as described for the cloning of HER2/HER3 promoters [ 22 , 24 ]. Briefly, approximately 1.5 kb proximal promoter region of HER1 was isolated, cloned, and used in the current study.…”

“…However, in the majority of such studies, the focus was on the regulation of NRF2 activity and its function by these kinases. While the interaction and complex formation of NRF2 with HER2 have been reported to enhance HER signalling [ 22 , 24 ], we recently demonstrated the transcriptional regulation of HER2 and HER3 by NRF2 [ 22 ]. Further, we demonstrated a relationship between NRF2 function, HER2/HER3 signalling, ROS generation, and the sensitisation of ovarian cancer cells to the killing effects of the targeted therapeutics, trastuzumab, pertuzumab, or their combination [ 22 , 24 ].…”