title: The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma.
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.
authors.affiliation: Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Emmy D G
authors.initials: ED
authors.lastname: Fleuren
authors.affiliation: Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Melissa H S
authors.initials: MH
authors.lastname: Hillebrandt-Roeffen
authors.affiliation: Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Uta E
authors.initials: UE
authors.lastname: Flucke
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: D Maroeska W M
authors.initials: DM
authors.lastname: Te Loo
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.affiliation: Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.affiliation: Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Yvonne M H
authors.initials: YM
authors.lastname: Versleijen-Jonkers
mesh_terms: D000293:Adolescent; D000328:Adult; D001567:Benzocycloheptenes / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000201:enzymology; D014230:Triazoles / Q000494:pharmacology*; D055815:Young Adult; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001567:Benzocycloheptenes; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D014230:Triazoles; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C548378:bemcentinib; C000722289:AXL protein, human