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Updated: Jan 30, 2026

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
11:34

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers

Published on: December 5, 2017

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Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast

Martin Schwill1, Rastislav Tamaskovic1, Aaron S Gajadhar2

  • 1Department of Biochemistry, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.

Science Signaling
|January 24, 2019
PubMed

Insights

Acquired resistance to HER2-targeted therapies involves adaptive kinase rewiring. Identifying key kinases like FAK1, PRKCD, and EPH receptors could help prevent drug resistance in HER2-overexpressing cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Acquired resistance to cancer therapies often arises from drug-induced signaling pathway rewiring.
  • Human epidermal growth factor receptor 2 (HER2)-targeted therapies are crucial for HER2-overexpressing cancers but can elicit adaptive resistance.
  • Understanding the adaptive kinase response is vital for overcoming treatment resistance.

Purpose of the Study:

  • To analyze the adaptive kinase response in cancer cells following distinct treatments targeting HER2.
  • To differentiate cancer cell fates based on treatment-induced signaling signatures.
  • To identify potential therapeutic targets to overcome adaptive resistance to HER2-targeted therapies.

Main Methods:

  • Quantitative phosphoproteomics using tandem mass tag (TMT) liquid chromatography/tandem mass spectrometry (LC-MS/MS).
  • Analysis of kinase activation using a bait peptide chip array.
  • System-wide analysis integrating phosphoproteome and kinase activation data.

Main Results:

  • A distinct signature of persistently phosphorylated tyrosine peptides was identified, differentiating nonapoptotic from apoptotic treatment outcomes.
  • Activation of focal adhesion kinase 1 (FAK1), protein kinase C-δ (PRKCD), and Ephrin (EPH) family receptors was identified as a common adaptive kinase response program.
  • Specific kinase activation patterns correlated with different treatment-induced cancer cell fates.

Conclusions:

  • Adaptive kinase reprogramming is a key mechanism in acquired resistance to HER2-targeted therapies.
  • FAK1, PRKCD, and EPH receptors represent potential targets to overcome adaptive resistance.
  • Targeting these adaptive pathways may improve the efficacy of HER2-targeted treatments.

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