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Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis

Benjamin Ruprecht1,2, Esther A Zaal3, Jana Zecha1,4,5

  • 1Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.

Cancer Research
|February 18, 2017
PubMed

Insights

Lapatinib resistance in HER2-positive breast cancer involves complex signaling changes. Multi-omic analysis reveals novel targets and highlights altered glycolysis as a key adaptation, suggesting new therapeutic strategies.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • HER2/ERBB2-overexpressing breast cancers are often treated with lapatinib.
  • Acquired resistance to lapatinib is a significant clinical challenge.

Purpose of the Study:

  • To investigate proteome, kinome, and phosphoproteome changes in lapatinib-resistant breast cancer.
  • To identify mechanisms of resistance and potential therapeutic targets.

Main Methods:

  • Explorative mass spectrometry was used to profile proteomic, kinomic, and phosphoproteomic changes.
  • Quantitative data was obtained for over 7,800 proteins, 300 kinases, and 15,000 phosphopeptides.

Main Results:

  • Previously known resistance mechanisms like AXL overexpression and PIK3 reactivation were confirmed.
  • Novel pharmacologically actionable targets were identified.
  • A significant phosphorylation-mediated reprogramming of glycolytic activity was discovered, with corresponding metabolic changes and increased sensitivity to glycolysis inhibition.

Conclusions:

  • Multi-omic analysis provides deep insights into cancer drug resistance.
  • The findings suggest new biomarkers and treatment options for lapatinib-resistant cancers.
  • Targeting altered glycolysis represents a potential therapeutic strategy.

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