2026-04-18T07:08:33Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2180172025-12-04T07:12:04Zcom_2072_1057col_2072_478858col_2072_478917col_2072_478921

Tumor Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation 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 Resistència als medicaments Fibroblasts Transducció de senyal cel·lular Dianes farmacològiques Càncer de mama Drug resistance Fibroblasts Cellular signal transduction Drug targeting Breast cancer 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. 2025-01-27T15:30:42Z 2025-01-27T15:30:42Z 2019-11-07 2025-01-27T15:30:42Z info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion Versió postprint del document publicat a: https://doi.org/10.1158/1078-0432.CCR-19-0353 Clinical Cancer Research, 2019, vol. 26, num.6, p. 1432-1448 https://doi.org/10.1158/1078-0432.CCR-19-0353 (c) American Association for Cancer Research, 2019 info:eu-repo/semantics/openAccess American Association for Cancer Research Articles publicats en revistes (Medicina)