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Updated: Aug 9, 2025

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics

Published on: March 15, 2024

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Integrin αvβ3 Is a Master Regulator of Resistance to TKI-Induced Ferroptosis in HER2-Positive Breast Cancer

Aadya Nagpal1,2,3,4, Kristen Needham1,2,5, Darius J R Lane6

  • 1Matrix Microenvironment & Metastasis Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.

Cancers
|February 25, 2023
PubMed

Insights

Resistance to HER2-targeting therapies in breast cancer is linked to ferroptosis resistance. Targeting αvβ3 integrin overcomes this resistance by re-wiring iron metabolism and AKT signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • HER2-targeting therapies are vital for HER2-positive breast cancer but face resistance.
  • Resistance to these therapies leads to disease relapse and treatment failure.
  • HER2 tyrosine kinase inhibitors (TKIs) induce ferroptosis, an iron-dependent cell death.

Purpose of the Study:

  • Investigate mechanisms of resistance to TKI-induced ferroptosis.
  • Identify novel strategies to overcome TKI resistance in HER2-positive breast cancer.

Main Methods:

  • Utilized mouse and human HER2-positive models with acquired TKI resistance.
  • Investigated the role of αvβ3 integrin in mediating resistance.
  • Analyzed iron/antioxidant metabolism and AKT signaling pathways.
  • Employed gene manipulation and pharmacological inhibitors.

Main Results:

  • Established a direct link between resistance to TKIs and resistance to ferroptosis.
  • Identified αvβ3 integrin as a key mediator of resistance to TKI-induced ferroptosis.
  • Demonstrated that αvβ3 integrin-mediated resistance involves altered iron/antioxidant metabolism and sustained AKT activation.
  • Showed that targeting αvβ3 integrin ('addiction') can reverse TKI resistance.

Conclusions:

  • αvβ3 integrin plays a critical role in mediating resistance to HER2-targeted therapies via ferroptosis.
  • Targeting αvβ3 integrin presents a promising therapeutic strategy to overcome treatment resistance.
  • Findings offer new insights for improving treatment outcomes in advanced HER2-positive breast cancer.
Keywords:
HER2-positive breast cancercell adhesion receptorsdrug resistanceferroptosistyrosine kinase inhibitorsαvβ3 integrin

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