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Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Glorianne Lazaro1, Chris Smith, Lindy Goddard

  • 1School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, UK.

Endocrine-Related Cancer
|August 1, 2013
PubMed

Insights

Targeting focal adhesion kinase (FAK) with PF4554878 synergistically enhances trastuzumab efficacy in HER2-positive breast cancer. This approach shows promise for overcoming resistance and restoring sensitivity in refractory cases.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Human Epidermal growth factor Receptor 2 (HER2) is a key target in breast cancer therapy, but resistance to anti-HER2 agents like trastuzumab is common.
  • Focal Adhesion Kinase (FAK) signaling is implicated in HER2 pathways and crosstalk with other growth factor receptors, potentially contributing to resistance.
  • Estrogen Receptor-positive (ER+)/HER2+ breast cancer presents a specific challenge where HER2 status influences treatment response.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting FAK using a novel FAK-specific inhibitor (PF4554878, PF878) in ER+/HER2+ breast cancer.
  • To evaluate the efficacy of PF878 as a monotherapy and in combination with trastuzumab.
  • To understand the molecular mechanisms underlying FAK inhibition's effects on HER2-driven signaling and cell proliferation.

Main Methods:

  • Assessed FAK/HER2 pathway activation in ER+/HER2- and ER+/HER2+ breast cancer cell lines.
  • Treated cells with PF878 alone and in combination with trastuzumab.
  • Utilized MTT assays, Coulter counting, and isobologram analysis to determine effects on cell growth and synergy.
  • Measured Akt activity and poly(ADP-ribose) polymerase (PARP) cleavage to assess downstream signaling.

Main Results:

  • FAK activation (Y861) was highest in ER+/HER2+ cells, which were most sensitive to PF878.
  • PF878 monotherapy inhibited heregulin-induced cell migration but not cell growth.
  • Combination therapy of PF878 and trastuzumab synergistically inhibited cell proliferation in ER+/HER2+ cells.
  • This synergistic effect was associated with abrogated Akt activity and increased PARP cleavage, particularly in trastuzumab-refractory cells.

Conclusions:

  • FAK plays a significant role in ER+/HER2+ breast cancer, and its inhibition can enhance trastuzumab response.
  • Targeting FAK with PF878 offers a potential strategy to overcome trastuzumab resistance.
  • FAK inhibition may restore trastuzumab sensitivity in refractory ER+/HER2+ breast cancer, highlighting its therapeutic importance.
Keywords:
HER2breast cancerfocal adhesion kinasehuman epidermal growth factor receptor 2luminal B breast cancertrastuzumab

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