The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma
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Emmy D.G. Fleuren1, Melissa H.S. Hillebrandt-Roeffen1, Uta E. Flucke2, D. Maroeska W.M. te Loo3, Otto C. Boerman4, Winette T.A. van der Graaf1, Yvonne M.H. Versleijen-Jonkers1
1Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands
2Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands
3Department of Pediatric Hematology and Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands
4Department of Radiology and Nuclear Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands
Emmy D.G. Fleuren, e-mail: Emmy.Fleuren@radboudumc.nl
Keywords: AXL, Gas6, Ewing sarcoma, BGB324, R428
Received: July 07, 2014 Accepted: October 27, 2014 Published: November 15, 2014
New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples. Low, medium and high AXL mRNA expression was observed in 31% (n = 9), 48% (n = 14) and 21% (n = 6) of samples. Gas6 was abundantly present in all specimens. We next tested AXL protein expression immunohistochemically in 36 tumors (primary, post-chemotherapy, metastasized and relapsed samples) from 25 ES patients. Low, medium and high AXL protein expression was observed in 17% (n = 6), 19% (n = 7) and 36% (n = 13) of samples. In primary tumors (n = 15), high AXL expression correlated significantly with a worse overall survival compared to patients with lower expression (61 vs. 194 months, p = 0.026). No genetic aberrations were detected in the AXL RTK domain (n = 29). The AXL-inhibitor BGB324 affected viability (IC50 0.79–2.13 μmol/L) and migratory potential of all tested ES cell lines in vitro (n = 5–6). BGB324 chemosensitized chemotherapy-resistant ES-4 cells to vincristine and doxorubicin. These data suggest that AXL is a potential novel, druggable therapeutic target in ES.
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