Skip to content

Research at St Andrews

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

Research output: Contribution to journalArticle


Hilal S. Khalil, Simon P. Langdon, Alexey Goltsov, Tero Soininen, David James Harrison, James Brown, Yusuf Y. Deeni

School/Research organisations


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.


Original languageEnglish
Pages (from-to)75874-75901
Issue number46
Early online date4 Oct 2016
Publication statusPublished - 2016

    Research areas

  • Pertuzumab/trastuzamab, NRF2, ROS, HER2-targeted, Cancer-immunotherapeutics

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. The landscape of genomic copy number alterations in colorectal cancer and their consequences on gene expression levels and disease outcome

    Ried, T., Meijer, G. A., Harrison, D. J., Grech, G., Franch-Expósito, S., Briffa, R., Carvalho, B. & Camps, J., 6 Aug 2019, In : Molecular Aspects of Medicine. 69, p. 48-61 14 p.

    Research output: Contribution to journalArticle

  2. Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031

    Sarr, A., Bré, J., Um, I. H., Chan, T. H., Mullen, P., Harrison, D. J. & Reynolds, P. A., 21 May 2019, In : Scientific Reports. 9, 13 p., 7643.

    Research output: Contribution to journalArticle

  3. Raman spectroscopy investigation of biochemical changes in tumor spheroids with aging and after treatment with staurosporine

    Jamieson, L. E., Harrison, D. J. & Campbell, C. J., May 2019, In : Journal of Biophotonics. 12, 5, e201800201.

    Research output: Contribution to journalArticle

Related by journal

  1. A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT

    Brown, J. L., Shovman, M., Robertson, P., Boiko, A., Goltsov, A., Mullen, P. & Harrison, D. J., May 2017, In : Oncotarget. 8, 18, p. 29657-29667 11 p.

    Research output: Contribution to journalArticle

  2. Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells

    Meehan, J., Ward, C., Turnbull, A., Bukowski-Wills, J., Finch, A., Jarman, E. J., Xintaropoulou, C., Martinez-Perez, C., Gray, M., Pearson, M., Mullen, P., Supuran, C. T., Carta, F., Harrison, D. J., Kunkler, I. H. & Langdon, S., 2017, In : Oncotarget. 8, 26, p. 42857-42875

    Research output: Contribution to journalArticle

  3. Delta-9-tetrahydrocannabinol protects against MPP+ toxicity in SH-SY5Y cells by restoring proteins involved in mitochondrial biogenesis

    Zeissler, M-L., Eastwood, J., McCorry, K., Hanemann, C. O., Zajicek, J. P. & Carroll, C. B., 27 Jun 2016, In : Oncotarget. 7, 29, p. 46603-46614 12 p.

    Research output: Contribution to journalArticle

  4. Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer

    Stewart, G. D., Powles, T., Van Neste, C., Meynert, A., O'Mahony, F., Laird, A., Deforce, D., Van Nieuwerburgh, F., Trooskens, G., Van Criekinge, W., De Meyer, T. & Harrison, D. J., 23 Mar 2016, In : Oncotarget. 7, 18, 10 p.

    Research output: Contribution to journalArticle

ID: 246403193