期刊
SCIENCE ADVANCES
卷 8, 期 20, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abk2746
关键词
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资金
- Asociacion Espanola contra el Cancer AECC [PRDVA18013LLUC, POSTD211413AREN, AECC_Postdoctoral17-1062]
- Spanish Government [PFIS FI20/00188]
- Breast Cancer Research Foundation [BCRF-20-08]
- Instituto de Salud Carlos III [AC15/00062, CB16/12/00449, PI19/01181]
- EC
- FEDER
- Asociacion Espanola Contra el Cancer (AECC)
- Instituto de Salud Carlos [III-PI19/01846]
- Breast Cancer Now- [2018NOVPCC1294]
- Instituto de Salud Carlos III
- FEDER [PI18/01219, CB16/12/00481]
- Sociedad Espanola de Oncologia Medica (Rio Hortega-SEOM)
- Compromiso ADAMED
AXL overexpression is identified as an essential mechanism of trastuzumab resistance in HER2-positive breast cancer, and targeting AXL can restore trastuzumab response. AXL may serve as a predictive biomarker for prognosis in HER2-positive breast cancer patients. The study emphasizes the importance of targeting AXL in combination with anti-HER2 drugs to overcome resistance.
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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