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

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

Research output: Contribution to journalArticle

11 Citations (Scopus)
15 Downloads (Pure)

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 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.
Original languageEnglish
Pages (from-to)75874-75901
Number of pages28
JournalOncotarget
Volume7
DOIs
Publication statusPublished - 4 Oct 2016

Fingerprint

Ovarian Neoplasms
Immunotherapy
Antibodies
Methylation
Antioxidants
Neoplasms
Histone Deacetylase Inhibitors
Receptor Protein-Tyrosine Kinases
Growth
Drug Resistance
Glutathione
Reactive Oxygen Species
Down-Regulation
Monoclonal Antibodies
Cell Line
Pharmaceutical Preparations
Trastuzumab
pertuzumab
Therapeutics

Cite this

Khalil, Hilal S. ; Langdon, Simon P. ; Goltsov, Alexey ; Soininen, Tero ; Harrison, David J. ; Bown, James L. ; Deeni, Yusuf Y. / A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells. In: Oncotarget. 2016 ; Vol. 7. pp. 75874-75901.
@article{32cbaceffce14dd3b76cd63e6c70bafc,
title = "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 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.",
author = "Khalil, {Hilal S.} and Langdon, {Simon P.} and Alexey Goltsov and Tero Soininen and Harrison, {David J.} and Bown, {James L.} and Deeni, {Yusuf Y.}",
year = "2016",
month = "10",
day = "4",
doi = "10.18632/oncotarget.12425",
language = "English",
volume = "7",
pages = "75874--75901",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",

}

A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells. / Khalil, Hilal S.; Langdon, Simon P.; Goltsov, Alexey; Soininen, Tero; Harrison, David J.; Bown, James L.; Deeni, Yusuf Y.

In: Oncotarget, Vol. 7, 04.10.2016, p. 75874-75901.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

AU - Khalil, Hilal S.

AU - Langdon, Simon P.

AU - Goltsov, Alexey

AU - Soininen, Tero

AU - Harrison, David J.

AU - Bown, James L.

AU - Deeni, Yusuf Y.

PY - 2016/10/4

Y1 - 2016/10/4

N2 - 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 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.

AB - 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 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.

U2 - 10.18632/oncotarget.12425

DO - 10.18632/oncotarget.12425

M3 - Article

VL - 7

SP - 75874

EP - 75901

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

ER -