Portal de investigación
Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer.
Fecha de publicación:
Fecha Ahead of Print:
Autores de INCLIVA
Participantes ajenos a INCLIVA
- Arenas, EJ
- Martinez-Sabadell, A
- Braso-Maristany, F
- Cervera, R
- Simon, S
- Poveda, J
- Moragon, S
- Zazo, S
- Martinez, D
- Rovira, A
- Rojo, F
- Albanell, J
- Prat, A
- Arribas, J
Grupos y Plataformas de I+D+i
Abstract
Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, AXL expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in AXL expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high AXL expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer.
Datos de la publicación
- ISSN/ISSNe:
- 2375-2548, 2375-2548
- Tipo:
- Article
- Páginas:
- -
- PubMed:
- 35594351
Science Advances American Association for the Advancement of Science
Citas Recibidas en Web of Science: 41
Documentos
Filiaciones
Financiación
Proyectos y Estudios Clínicos
INCORPORACIÓN DE NUEVAS ÁREAS TEMÁTICAS Y NUEVOS GRUPOS AL CONSORCIO CIBER
Investigador Principal: ANA LLUCH HERNÁNDEZ
CB16/12/00481 . INSTITUTO SALUD CARLOS III
Caracterizacion y repercusion terapeutica de la ecologia de cancer de mama HER2 positivo
Investigador Principal: PILAR EROLES ASENSIO
PI18/01219 . INSTITUTO SALUD CARLOS III . 2019
Cita
Adam A,Arenas EJ,Martinez A,Braso F,Cervera R,Tormo E,Hernando C,Martinez MT,Carbonell J,Simon S,Poveda J,Moragon S,Zazo S,Martinez D,Rovira A,Burgues O,Rojo F,Albanell J,Bermejo B,Lluch A,Prat A,Arribas J,Eroles P,Cejalvo JM. Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. Sci. Adv. 2022. 8. (20):eabk2746. IF:13,600. (1).
Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. Adam A, Arenas EJ, Martinez A, Braso F, Cervera R, Tormo E, Hernando C et al. Science Advances. 2022 mayo 20. 8 (20):DOI:10.1126/sciadv.abk2746. PMID:35594351.
