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RESEARCH PRODUCT

The role of AXL as mechanism of resistance to trastuzumab and a prognostic factor in breast cancer HER2 positive: A translational approach

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Abstract Background Breast cancer (BC) is a heterogeneous disease. HER2+ BC represents between 15-30% of cases. Trastuzumab (T), a monoclonal antibody, has been successfully improved clinical benefits in both adjuvant and in metastatic settings. Despite this evidence, many patients experience resistance to therapy. The objective of this study is to assess AXL as a potential mechanism of resistance and its implication as a prognostic factor. Methods We used three cell lines with acquired resistance to T. Resistant models were generated by treating parental cells (AU565, SKR3, BT474) with constant dose of T (15mg/mL) for 6 months. Cell viability was estimated by MTT assay. Proteins were assessed by Western blot (WB) and flow cytometry and genes by qRT-PCR. AXL was downregulated by siRNA and a selective AXL inhibitor (TP-0903). The prognostic value of AXL was evaluated in primary tumor in a cohort of HER2+ BC patients treated with T in adjuvant setting from Hospital Clinico Valencia (n = 33). Results Acquired resistant cell lines (RCL) maintained HER2 overexpression. Cells were more proliferative and presented an increase in stem cell-like characteristics compared to sensitive parental cell lines. There was an important up-regulation of AXL (>2.5 fold-change) and epithelial-mesenchymal transition markers (VIM, CDH2, and FN1) in RCL (p  Conclusions Our results suggest: 1) RCL were more proliferative, more mesenchymal-like and stem cell-like properties; 2) AXL was a potential mechanism of secondary resistance to T; 3) Combination therapy with AXL inhibitor plus T restored sensitivity in in vitro model with AXL overexpression; 4) AXL expression was associated with relapse in HER2+ BC patients. These results showed AXL as a prognostic factor and a potential therapeutic target in HER2+ patients with resistance to T. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure A. Lluch: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Eisai; Advisory / Consultancy: Celgene. All other authors have declared no conflicts of interest.