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Updated: Jan 4, 2026
09:01
Cancer-Associated Fibroblasts from Mouse Mammary Tumors as Tools for Molecular and Computational Studies
Published on: July 3, 2025
785
Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation
Patricia Fernández-Nogueira1,2, Mario Mancino1,2, Gemma Fuster1
1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Summary
Tumor-associated fibroblasts (TAFs) drive resistance to HER2-targeted therapies by secreting FGF5, activating FGFR2, and creating a feedback loop. FGFR2 inhibitors can overcome this resistance and resensitize tumors to HER2-targeted treatments.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Existing HER2-targeted therapies are effective but tumors frequently develop resistance.
- Understanding resistance mechanisms is crucial for improving breast cancer treatment outcomes.
Purpose of the Study:
- To identify novel mechanisms driving resistance to HER2-targeted therapies.
- To investigate the role of tumor-associated fibroblasts (TAFs) in mediating this resistance.
Main Methods:
- Utilized HER2-targeted therapy-resistant cell lines and primary fibroblast cultures.
- Investigated the TAF/FGF5/FGFR2/c-Src/HER2 signaling axis.
- Validated findings in preclinical models and patient samples.
Main Results:
- TAFs promote resistance by secreting FGF5, activating FGFR2, which then transactivates HER2 via c-Src.
- A positive feedback loop between cancer cells and TAFs fuels resistance.
- FGFR2 inhibition reversed resistance, induced apoptosis, and resensitized tumors to HER2-targeted therapies in vivo.
- FGF5 and FGFR2 expression correlated with poor outcomes in HER2-positive breast cancer patients.
Conclusions:
- The TAF/FGF5/FGFR2/c-Src/HER2 axis is a key escape pathway in HER2-targeted therapy resistance.
- FGFR2 inhibitors represent a promising strategy to overcome resistance and improve treatment efficacy.
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