Portal de investigación
Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation
Fecha de publicación:
Fecha Ahead of Print:
Autores de INCLIVA
Participantes ajenos a INCLIVA
- Fernandez-Nogueira, P
- Mancino, M
- Fuster, G
- Lopez-Plana, A
- Jauregui, P
- Almendro, V
- Enreig, E
- Menendez, S
- Rojo, F
- Noguera-Castells, A
- Bill, A
- Gaither, LA
- Serrano, L
- Recalde-Percaz, L
- Moragas, N
- Alonso, R
- Ametller, E
- Rovira, A
- Albanell, J
- Gascon, P
- Bragado, P
Grupos y Plataformas de I+D+i
Abstract
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, alpha-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.
© 2019 American Association for Cancer Research.
Datos de la publicación
- ISSN/ISSNe:
- 1078-0432, 1557-3265
- Tipo:
- Article
- Páginas:
- 1432-1448
- PubMed:
- 31699826
CLINICAL CANCER RESEARCH AMER ASSOC CANCER RESEARCH
Citas Recibidas en Web of Science: 68
Documentos
Filiaciones
Proyectos y Estudios Clínicos
RED TEMÁTICA DE INVESTIGACIÓN COOPERATIVA
Investigador Principal: ANA LLUCH HERNÁNDEZ
RD12/0036/0070 . INSTITUTO SALUD CARLOS III . 2014
Papel de la heterogeneidad tumoral y la reprogramación dinámica de la célula tumoral en la resistencia a anticuerpos anti-HER2 en cáncer de mama HER2 positivo
Investigador Principal: ANA LLUCH HERNÁNDEZ
PI15/01617 . INSTITUTO SALUD CARLOS III . 2016
Cita
Fernandez P,Mancino M,Fuster G,Lopez A,Jauregui P,Almendro V,Enreig E,Menendez S,Rojo F,Noguera A,Bill A,Gaither LA,Serrano L,Recalde L,Moragas N,Alonso R,Ametller E,Rovira A,Lluch A,Albanell J,Gascon P,Bragado P. Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation. Clin. Cancer Res. 2020. 26. (6):p. 1432-1448. IF:12,531. (1).
Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation. Fernandez P, Mancino M, Fuster G, Lopez A, Jauregui P, Almendro V, Enreig E et al. CLINICAL CANCER RESEARCH. 2020 marzo 01. 26 (6):1432-1448. DOI:10.1158/1078-0432.CCR-19-0353. PMID:31699826.
