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2019-11-07

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/218017

Tumor Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation

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https://doi.org/10.1158/1078-0432.CCR-19-0353

Resum

Purpose: 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. Experimental design: 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. Results: 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. Conclusions: 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.

Matèries

Resistència als medicaments, Fibroblasts, Transducció de senyal cel·lular, Dianes farmacològiques, Càncer de mama

Matèries (anglès)

Drug resistance, Fibroblasts, Cellular signal transduction, Drug targeting, Breast cancer

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Articles publicats en revistes (Medicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Citació

FERNÁNDEZ NOGUEIRA, Patricia, MANCINO, Mario, FUSTER ORELLANA, Gemma, LÓPEZ PLANA, Anna, JAUREGUI, Patricia, ALMENDRO NAVARRO, Vanessa, ENREIG, Estel, MENÉNDEZ, Silvia, ROJO, Federico, NOGUERA CASTELLS, Aleix, BILL, Anke, GAITHER, L. alex, SERRANO, Laia, RECALDE PERCAZ, Leire, MORAGAS GARCIA, Núria, ALONSO, Raul, AMETLLER, Elisabet, ROVIRA, Ana, LLUCH, Ana, ALBANELL MESTRES, Joan, GASCON, Pere, BRAGADO DOMINGO, Paloma. Tumor Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation. _Clinical Cancer Research_. 2019. Vol. 26, núm. 6, pàgs. 1432-1448. [consulta: 21 de gener de 2026]. ISSN: 1078-0432. [Disponible a: https://hdl.handle.net/2445/218017]

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