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NRF2 Regulates HER2 and HER3 Signaling Pathway to Modulate Sensitivity to Targeted Immunotherapies

Hilal S Khalil1, Simon P Langdon2, Ibrahim H Kankia1

  • 1SIMBIOS, School of Science, Engineering and Technology, Abertay University, Dundee DD1 1HG, UK.

Oxidative Medicine and Cellular Longevity
|January 16, 2016
PubMed

Insights

The transcription factor NRF2 (NF-E2 related factor-2) promotes ovarian cancer cell proliferation and resistance to HER2-targeted therapies by upregulating HER2 and HER3 receptors. Inhibiting NRF2 may enhance cancer treatment efficacy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • NF-E2 related factor-2 (NRF2) is a transcription factor regulating antioxidant and detoxification genes.
  • NRF2 is linked to cancer therapeutic resistance through its functions and interactions with proliferative pathways.
  • The precise mechanism connecting NRF2 and growth factor-induced proliferation in cancer is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism of crosstalk between NRF2 and growth factor-induced proliferative pathways in ovarian cancer.
  • To investigate the role of NRF2 in regulating HER2 and HER3 receptors and their response to HER2-targeting therapies.

Main Methods:

  • Pharmacological activation of NRF2 using tert-butylhydroquinone (tBHQ).
  • Assessment of HER2, HER3 expression, and pAKT levels.
  • Evaluation of ovarian cancer cell proliferation and response to HER2-targeting monoclonal antibodies (Pertuzumab, Trastuzumab).
  • NRF2 knockdown using siRNA and subsequent analysis of gene expression and drug sensitivity.

Main Results:

  • Pharmacological NRF2 activation upregulated HER2 and HER3 expression, increased pAKT levels, and enhanced ovarian cancer cell proliferation.
  • NRF2 activation reduced the efficacy of combined Pertuzumab and Trastuzumab treatment.
  • tBHQ induced HER2 and HER3 transcription; NRF2 knockdown prevented this induction, repressed transcription, and increased HER2 inhibitor cytotoxicity.

Conclusions:

  • NRF2 regulates HER2 and HER3 receptor expression, influencing cellular responses to HER2-targeting monoclonal antibodies.
  • The identified NRF2-HER2/HER3 crosstalk mechanism contributes to drug resistance in ovarian cancer.
  • NRF2 represents a potential therapeutic target for overcoming resistance to HER2-targeted cancer therapies.

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