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

Date

29 Sep 2019

Session

Poster Display session 2

Presenters

Anna Adam-Artigues

Citation

Annals of Oncology (2019) 30 (suppl_5): v104-v142. 10.1093/annonc/mdz242

Authors

A. Adam-Artigues1, E. Tormo2, F. Rojo3, J.A. Perez-Fidalgo2, S. Zazo4, P. Gonzalez-Alonso4, C. Hernando5, M.T. Martínez1, V. Gambardella1, J. Poveda5, S. Simón5, S. Moragon5, E. Alonso6, A. Rovira7, J. Albanell7, O. Burgues6, B. Bermejo8, P. Eroles2, A. Lluch8, J.M. Cejalvo1

Author affiliations

  • 1 Medical Oncology Departament., Biomedical Research Institute INCLIVA, Hospital Clínico València, University of Valencia, 46010 - Valencia/ES
  • 2 Medical Oncology Departament., Biomedical Research Institute INCLIVA, Hospital Clínico València, University of Valencia. Center for Biomedical Network Research on Cancer (CIBERONC), 46010 - Valencia/ES
  • 3 Pathology Department, IIS-Fundación Jiménez Díaz. Center for Biomedical Network Research on Cancer (CIBERONC), Madrid/ES
  • 4 Pathology Department, IIS-Fundación Jiménez Díaz, Madrid/ES
  • 5 Medical Oncology Departament., Biomedical Research Institute INCLIVA, Hospital Clínico València, University of Valencia, Valencia/ES
  • 6 Pathology, Hospital Clínico Valencia, University of Valencia, Valencia/ES
  • 7 Medical Oncology Departament., University Hospital del Mar. Center for Biomedical Network Research on Cancer (CIBERONC), 8003 - Barcelona/ES
  • 8 Medical Oncology Departament., Biomedical Research Institute INCLIVA, Hospital Clínico València, University of Valencia. Center for Biomedical Network Research on Cancer (CIBERONC), Valencia/ES
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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 Clínico València (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 < 0.05). Sensibility to T was restored by silencing AXL and with TP-0903 treatment decreasing cell viability and IC50 of T (p < 0.05). AXL expression was associated with metastasis in a cohort of HER2+ BC patients (p < 0.001). There was no difference in GAS6 (a ligand of AXL). The role of AXL was also evaluated in a public data set and it was related with worse prognosis (p < 0.001).

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.

Clinical trial identification

Editorial acknowledgement

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.

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