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

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Date
2016
Author
Khalil, Hilal S.
Langdon, Simon P.
Goltsov, Alexey
Soininen, Tero
Harrison, David James
Brown, James
Deeni, Yusuf Y.
Keywords
Pertuzumab/trastuzamab
NRF2
ROS
HER2-targeted
Cancer-immunotherapeutics
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
QA75 Electronic computers. Computer science
QH301 Biology
NDAS
SDG 3 - Good Health and Well-being
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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 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.
Citation
Khalil , 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 . https://doi.org/10.18632/oncotarget.12425
Publication
Oncotarget
Status
Peer reviewed
DOI
https://doi.org/10.18632/oncotarget.12425
ISSN
1949-2553
Type
Journal article
Rights
Copyright 2016 the Author(s). Licensed under a Creative Commons Attribution 3.0 License.
Description
This 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).
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/9663

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