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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
07:42

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

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Crosstalk between ERα and Receptor Tyrosine Kinase Signalling and Implications for the Development of Anti-Endocrine

Rugaia Z Montaser1, Helen M Coley2

  • 1Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. rugaia.montaser@gmail.com.

Cancers
|June 22, 2018
PubMed

Insights

Acquired resistance to anti-endocrine therapies in breast cancer can be overcome. Tyrosine kinase inhibitors (TKIs) like afatinib show promise in combination treatments, enhancing apoptosis and overcoming resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Anti-endocrine therapies are crucial for estrogen receptor (ER)-expressing breast cancer but acquired drug resistance remains a significant clinical challenge.
  • Breast cancer cell lines (MCF-7, T47D) and their tamoxifen-resistant (MCF-7-TR) and fulvestrant-resistant (T47D-FR) counterparts exhibit dual resistance.
  • Upregulation of HER1 and HER2 growth factor receptors is observed in resistant cell lines.

Purpose of the Study:

  • To investigate the efficacy of tyrosine kinase inhibitors (TKIs) in overcoming acquired resistance to anti-endocrine therapies in ER-positive breast cancer.
  • To explore the potential of combining TKIs with existing anti-endocrine agents for enhanced therapeutic outcomes.
  • To understand the molecular mechanisms underlying TKI sensitivity and resistance in breast cancer.

Main Methods:

  • Utilized ER-positive breast cancer cell lines (MCF-7, T47D) and their in vitro derived resistant counterparts (MCF-7-TR, T47D-FR).
  • Assessed sensitivity to TKIs lapatinib and afatinib in resistant cell lines.
  • Investigated the effect of TKIs on ERα reactivation and combination therapy with anti-endocrine agents.
  • Measured apoptosis induction and p27kip1 levels in response to treatment.

Main Results:

  • Tamoxifen and fulvestrant resistance were associated with collateral sensitivity to TKIs lapatinib and afatinib (p < 0.0001).
  • TKIs reactivated ERα protein and/or mRNA in resistant cells over time.
  • Combination therapy of anti-endocrine agents with afatinib synergistically enhanced apoptosis in resistant cells compared to single agents.
  • p27kip1 induction was observed in anti-endocrine-resistant cells treated with combination therapy.

Conclusions:

  • Dual HER1/2 inhibitors like afatinib demonstrate efficacy in overcoming acquired resistance to multiple anti-endocrine agents in breast cancer.
  • Combination treatment strategies utilizing TKIs alongside anti-endocrine agents offer a promising approach for resistant breast cancer.
  • Targeting HER1/2 pathways can re-sensitize resistant breast cancer cells to endocrine therapy and induce significant apoptosis.
Keywords:
breast cancerdrug resistancereceptor tyrosine kinases

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