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Inhibiting ERK5 overcomes breast cancer resistance to anti-HER2 therapy by targeting the G1/S cell cycle transition

Jingwei Zhang1, Adam J Pearson1, Nitin Sabherwal2

  • 1Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health (FBMH), University of Manchester, UK.

Cancer Research Communications
|December 5, 2022
PubMed

Insights

Targeting human epidermal growth factor receptor 2 (HER2) is key for breast cancer. Inhibiting extracellular-regulated protein kinase 5 (ERK5) can overcome resistance to HER2 therapies, improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Targeting human epidermal growth factor receptor 2 (HER2) revolutionized HER2-positive breast cancer treatment.
  • Therapeutic resistance and metastasis remain significant challenges in HER2-driven breast cancer.
  • Constitutive activation of extracellular-regulated protein kinase 5 (ERK5) is a molecular consequence of HER2 oncogenic signaling.

Purpose of the Study:

  • To investigate the role of ERK5 in mediating resistance to anti-HER2 therapies.
  • To determine if inhibiting ERK5 can restore sensitivity to anti-HER2 agents.
  • To evaluate the therapeutic potential of combining ERK5 inhibitors with anti-HER2 therapies.

Main Methods:

  • Utilized small-molecule inhibitors and genetic knockdown (siRNA) to target ERK5.
  • Assessed the impact of ERK5 inhibition on retinoblastoma protein (RB) phosphorylation.
  • Evaluated cell proliferation and cell cycle progression (G1 arrest) in response to combined therapies.
  • Tested the efficacy of ERK5 inhibition in human breast cancer xenograft models.

Main Results:

  • ERK5 inhibition suppressed retinoblastoma protein (RB) phosphorylation in HER2-positive breast cancer cells.
  • Combined ERK5 inhibition and anti-HER2 therapy enhanced anti-proliferative effects and induced G1 cell cycle arrest in resistant cell lines.
  • ERK5 knockdown restored the anti-tumor activity of lapatinib in preclinical xenograft models.

Conclusions:

  • ERK5 signaling is a critical mediator of resistance to HER2-targeted therapies in breast cancer.
  • Inhibiting ERK5 represents a promising strategy to overcome therapeutic resistance.
  • Combining ERK5 inhibitors with existing anti-HER2 agents may improve clinical outcomes for patients with HER2-driven breast cancer.

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