title: Trk inhibitor attenuates the BDNF/TrkB-induced protection of neuroblastoma cells from etoposide in vitro and in vivo.
abstract: TrkB activation by brain-derived neurotrophic factor (BDNF) contributes to chemo-resistance in neuroblastoma (NB). AZD6918 is a novel potent and selective inhibitor of the Trk tyrosine kinases. In this study we evaluated the effect of AZD6918 on the sensitivity of TrkB-expressing NB cells or tumors to etoposide, a topoisomerase II inhibitor. TrkB-expressing NB cells were treated with AZD6918 and etoposide in the presence or absence of BDNF in vitro and cell survival was determined. NB xenograft tumors were treated with AZD6918 and etoposide, either alone or in combination in vivo, and the anti-tumor growth effect or mice survival advantage was evaluated. Our study showed that AZD6918 induced cell death as a single agent and attenuated BDNF/TrkB-induced protection from etoposide in vitro. Although AZD6918 alone didn't show anti-tumor growth effect or survival advantage in vivo, a combination of AZD6918 and etoposide had a statistically significant stronger anti-tumor growth effect and survival advantage compared to treatment with either agent alone. Our data indicate that as a Trk inhibitor AZD6918 increased the sensitivity of NB to etoposide. These results extend the spectrum of cytotoxic drugs whose efficacy is increased in combination with Trk inhibitors and support the combination of Trk inhibitors and cytotoxic drugs for NB treatment.
authors.affiliation: a Cell & Molecular Biology Section, Pediatric Oncology Branch , National Institutes of Health , Bethesda , MD , USA.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Tong
authors.forename: Jenna
authors.initials: J
authors.lastname: Tong
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Thiele
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005047:Etoposide / Q000008:administration & dosage; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D020813:Receptor, trkB
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D005047:Etoposide; C579455:BDNF protein, human; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human
keywords: AZD6918; BDNF, brain-derived neurotrophic factor; NB, neuroblastoma; TET, tetracycline; Trk inhibitor; Trk, tropomyosin-related kinase; etoposide; neuroblastoma