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Please use this identifier to cite or link to this item: 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, et al. Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. Science Advances. 2022. Vol. 8, num. 20. ISSN 2375-2548. [consulted: 7 of June of 2026]. Available at: https://hdl.handle.net/2445/197295