Overcoming resistance to HER2 blockade in breast cancer: AXL as a promising druggable target and prognostic biomarker

• Autores: Anna Adam Artigues
• Directores de la Tesis: Ana Lluch Hernández (dir. tes.), Pilar Eroles Asensio (codir. tes.)
• Lectura: En la Universitat de València ( España ) en 2022
• Idioma: inglés
• Tribunal Calificador de la Tesis: Andrés Cervantes Ruiperez (presid.), Roger R. Gomis (secret.), Erika Martineli (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina y Biotecnología por la Universitat de València (Estudi General)
• Materias:
  • Ciencias de la vida
• Enlaces
  • Tesis en acceso abierto en: TESEO
• Resumen

  • Anti-HER2 therapies have dramatically improved prognosis in HER2-positive breast cancer patients. However, around 20% of these patients develop resistance to therapies, leading to relapse and metastasis, which nowadays is considered incurable. In this context, several mechanisms have been described to play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of acquired resistance to trastuzumab in cell lines, organoids and in vivo patient-derived xenograft HER2-positive breast cancer models. Mechanistically, AXL orchestrated epithelial to mesenchymal transition, promoting a mesenchymal-like phenotype. Besides, AXL heterodimerized with HER2, which lead to activation of PI3K/AKT and MAPK/ERK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL decreased phosphorylation of these two pathways and restored trastuzumab response in in vitro and in vivo HER2-positive breast cancer models. Importantly, the combination of AXL inhibitor plus trastuzumab achieved complete regression of the tumor in trastuzumab-resistant patient-derived xenograft in vivo models with no evidence of tumor regrowth after a long period follow-up. Moreover, these animals presented a good quality of life with no symptoms of treatment toxicity. In the clinical setting, AXL mRNA expression in HER2-positive breast cancer primary tumor tissue was able to predict treatment response and was negatively associated with disease-free survival and overall survival. Data from the multicentre phase II PAMELA clinical trial showed a significant increase in AXL expression in tumor tissue during neoadjuvant dual HER2 blockade, supporting its role in resistance. In accordance with preclinical data, AXL showed direct correlation with VIM expression, however GAS6 expression was no related to prognosis in patient’s samples. These rapid changes in AXL expression upon trastuzumab resistance suggest increased transcription activity that could be performed by JUNB transcription factor. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs as a potential therapeutic strategy 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 treated with trastuzumab.