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Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
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Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

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Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer

Jichao He1, Ronan P McLaughlin1, Vera van der Noord1

  • 1Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.

Breast Cancer Research and Treatment
|August 8, 2019
PubMed
Abstract

Insights

This study found that combining AEE788 with mTOR inhibitors (rapalogs) effectively treats triple-negative breast cancer (TNBC) by overcoming resistance. This combination therapy targets key signaling pathways for improved TNBC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Triple-negative breast cancer (TNBC) presents significant treatment challenges due to genetic heterogeneity and acquired resistance.
  • Current single-targeted therapies are often ineffective against TNBC, leading to high mortality rates.

Purpose of the Study:

  • To explore combined targeted therapy strategies to overcome resistance in triple-negative breast cancer.
  • To identify effective drug combinations for treating refractory TNBC by blocking interactive oncogenic signaling networks.

Main Methods:

  • A kinase inhibitor screen identified TNBC cells' resistance to mammalian target of rapamycin (mTOR) inhibition.
  • A drug combination screen revealed that AEE788 (EGFR/HER2/VEGFR inhibitor) synergizes with rapalogs (rapamycin analogs) to inhibit TNBC proliferation.

Main Results:

  • Combination therapy with AEE788 and rapalogs inhibited mTOR signaling and sensitized TNBC cells to rapalogs.
  • This combination treatment suppressed key signaling pathways including AKT and ERK.
  • siRNA validation identified RPS6K members as synthetic lethal targets for combination therapy.

Conclusions:

  • mTOR signaling is highly activated in TNBC, and single rapalog treatment is insufficient.
  • A multi-kinase inhibitor combinatorial strategy using AEE788 and rapalogs offers a promising approach to overcome therapy resistance in TNBC.
Keywords:
Drug resistanceMulti-kinase inhibitorPolypharmacologyTriple-negative breast cancer (TNBC)mTOR-targeted therapy

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