Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer

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 an...

Descripción completa

Detalles Bibliográficos
Autores: Adam Artigues, Anna, Arenas Lahuerta, Enrique Javier, Martínez Sabadell, Alex, Brasó-Maristany, Fara, Cervera, Raimundo, Tormo, Eduardo, Hernando, Cristina, Martínez, Maria Teresa, Carbonell Asins, Juan, Simón, Soraya, Poveda, Jesús, Moragón, Santiago, Zazo, Sandra, Martínez, Débora, Rovira, Ana, Burgues, Octavio, Rojo, Federico, Albanell Mestres, Joan, Bermejo, Begoña, Lluch Hernández, Ana, Prat Aparicio, Aleix, Arribas, Joaquín, Eroles, Pilar, Cejalvo Andújar, Juan Miguel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/197295
Acceso en línea:https://hdl.handle.net/2445/197295
Access Level:acceso abierto
Palabra clave:Càncer de mama
Resistència als medicaments
Breast cancer
Drug resistance
Descripción
Sumario: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.

Similares en LA Referencia