Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer
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- dc.contributor.author Adam-Artigues, Anna
- dc.contributor.author Rovira Guerín, Ana
- dc.contributor.author Albanell Mestres, Joan
- dc.contributor.author Arribas, Joaquín
- dc.contributor.author Cejalvo, Juan M.
- dc.date.accessioned 2022-12-09T08:04:51Z
- dc.date.available 2022-12-09T08:04:51Z
- dc.date.issued 2022
- dc.description.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.
- dc.format.mimetype application/pdf
- dc.identifier.citation Adam-Artigues A, Arenas EJ, Martínez-Sabadell A, Brasó-Maristany F, Cervera R, Tormo E, et al. Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. Sci Adv. 2022 May 20; 8(20): eabk2746. DOI: 10.1126/sciadv.abk2746
- dc.identifier.doi http://dx.doi.org/10.1126/sciadv.abk2746
- dc.identifier.issn 2375-2548
- dc.identifier.uri http://hdl.handle.net/10230/55093
- dc.language.iso eng
- dc.publisher American Association for the Advancement of Science (AAAS)
- dc.rights Copyright © 2022 Adam-Artigues A, Arenas EJ, Martínez-Sabadell A, Brasó-Maristany F, Cervera R, Tormo E, et al, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, http://creativecommons.org/licenses/by-nc/4.0/ which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
- dc.subject.other Mama--Càncer
- dc.subject.other Càncer--Tractament
- dc.subject.other Tumors
- dc.title Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion