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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/197295
Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer
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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.
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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, Juan miguel. Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. _Science Advances_. 2022. Vol. 8, núm. 20. [consulta: 23 de gener de 2026]. ISSN: 2375-2548. [Disponible a: https://hdl.handle.net/2445/197295]