Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation
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- Patricia Fernández-Nogueira
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Mario Mancino
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Gemma Fuster
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Anna López-Plana
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Patricia Jauregui
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Vanesa Almendro
- 3Division of Medical Oncology, Department of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.
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- Estel Enreig
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Silvia Menéndez
- 4Pathology Department, Hospital del Mar, Barcelona, Spain.
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- Federico Rojo
- 5Pathology Department, CIBERONC- IIS-Fundación Jiménez Díaz, Madrid, Spain.
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- Aleix Noguera-Castells
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Anke Bill
- 6Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts.
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- L. Alex Gaither
- 6Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts.
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- Laia Serrano
- 4Pathology Department, Hospital del Mar, Barcelona, Spain.
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- Leire Recalde-Percaz
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Núria Moragas
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Raul Alonso
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Elisabet Ametller
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Ana Rovira
- 7Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Ana Lluch
- 9INCLIVA Biomedical Research Institute, Universitat de València, Valencia, Spain.
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- Joan Albanell
- 7Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Pere Gascon
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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- Paloma Bragado
- 1Molecular and Translational Oncology Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
抄録
<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose:</jats:title><jats:p>Despite the therapeutic success of existing HER2-targeted therapies, tumors invariably relapse. This study aimed at identifying new mechanisms responsible for HER2-targeted therapy resistance.</jats:p></jats:sec><jats:sec><jats:title>Experimental Design:</jats:title><jats:p>We have used a platform of HER2-targeted therapy–resistant cell lines and primary cultures of healthy and tumor-associated fibroblasts (TAF) to identify new potential targets related to tumor escape from anti-HER2 therapies.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p>We have shown that TAFs promote resistance to HER2-targeted therapies. TAFs produce and secrete high levels of FGF5, which induces FGFR2 activation in the surrounding breast cancer cells. FGFR2 transactivates HER2 via c-Src, leading to resistance to HER2-targeted therapies. In vivo, coinoculating nonresistant cell lines with TAFs results in more aggressive and resistant tumors. Resistant cells activate fibroblasts and secrete FGFR ligands, creating a positive feedback loop that fuels resistance. FGFR2 inhibition not only inhibits HER2 activation, but also induces apoptosis in cells resistant to HER2-targeted therapies. In vivo, inhibitors of FGFR2 reverse resistance and resensitize resistant cells to HER2-targeted therapies. In HER2 patients' samples, α-SMA, FGF5, and FGFR2 contribute to poor outcome and correlate with c-Src activation. Importantly, expression of FGF5 and phospho-HER2 correlated with a reduced pathologic complete response rate in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab, which highlights the significant role of TAFs/FGF5 in HER2 breast cancer progression and resistance.</jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p>We have identified the TAF/FGF5/FGFR2/c-Src/HER2 axis as an escape pathway responsible for HER2-targeted therapy resistance in breast cancer, which can be reversed by FGFR inhibitors.</jats:p></jats:sec>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 26 (6), 1432-1448, 2020-03-13
American Association for Cancer Research (AACR)