Abstract
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.
Highlights
Ewing sarcoma (ES) is a highly aggressive type of primary bone cancer, predominantly affecting children and adolescents
Compared to a panel of 80 breast carcinoma (BC) samples stained in parallel, including triple-negative samples and selected positive BC tissue controls, considerably higher AXL expression was observed in ES samples (Figure 1F)
We are the first to implicate AXL in ES. We demonstrated that both AXL and Growth-arrest-specific protein 6 (Gas6) are abundantly expressed in tumors of ES patients and that high AXL protein expression is an independent prognostic marker of poor OS
Summary
Ewing sarcoma (ES) is a highly aggressive type of primary bone cancer, predominantly affecting children and adolescents. Radiotherapy and polychemotherapy, the final outcome in patients with metastatic disease has not improved impressively during the last decades and side-effects of treatment could be severe [1, 2]. RTKs are membrane-bound proteins and are important regulators of cellular processes, such as cell growth, proliferation and survival. In addition to their pivotal role in normal physiology, several RTKs have been implicated in many human cancers [4]. Some RTKs have been implicated in ES, predominantly the Insulin-like Growth Factor-1 Receptor (IGF-1R), and more recently MET and Anaplastic Lymphoma Kinase (ALK), the role of several other RTKs remains to be elucidated [5,6,7,8]. We investigated the role of AXL in ES
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