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Published on: May 17, 2017
Effect of CEP-751 (KT-6587) on neuroblastoma xenografts expressing TrkB
A E Evans1, K D Kisselbach, X Liu
1Division of Oncology, Children's Hospital of Philadelphia, Pennsylvania 19104, USA. evansa@email.chop.edu
Background:
The compound CEP-751 (KT-6587), a potent and selective inhibitor of the Trk family of tyrosine kinases, has been shown to inhibit the growth of human neuroblastoma (NB) xenografts in nude mice [1].
Procedure:
To address its mechanism of action, we studied SY5Y, a human NB cell line with no detectable Trk expression, and two subclones transfected with TrkB. The transfected clones, SY5Y (G8) and SY5Y (G12), expressed moderate and high levels, respectively, of TrkB mRNA and protein. These TrkB-expressing subclones and the parental line were then grown as xenografts in nude mice, and CEP-751 was used to inhibit TrkB tyrosine kinase activity in these xenografts. Animals were treated twice a day with CEP-751 (21 mg/kg), or with the carrier vehicle as a control. TrkB expression in the resultant tumors was examined by quantitative RT-PCR. The effect of CEP-751 on TrkB activation by BDNF was examined in G12 cells in culture by immunoprecipitation with antipan Trk antiserum, followed by Western blot analysis using antiphosphotyrosine antibodies. To determine if CEP-751 was causing apoptosis, the TUNEL assay was used.
Results:
CEP-751 had little effect on the growth of SY5Y tumors, but did slow the growth rate of the C8 and G12 tumors. The daily growth rate of the treated tumors was 0.16, 0.13, and 0.10 cm3, respectively, for the SY5Y, G8, and G12 tumors. RT PCR analysis confirmed the expression of TrkB in G8 and G12, but not in SY5Y tumors. Activation of TrkB by BDNF in G12 cells was inhibited by CEP-751 in a dose dependent fashion. The treated tumors showed marked evidence of apoptosis.
Conclusions:
These data suggest that the effect of CEP-751 is due, at least in part, to its inhibition of TrkB kinase, and that CEP-751 may become a useful therapeutic tool for the treatment of aggressive neuroblastomas, which often express TrkB.
Insights
CEP-751, a Trk inhibitor, slowed neuroblastoma tumor growth by inducing apoptosis, particularly in TrkB-expressing cells. This suggests CEP-751
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- CEP-751 (KT-6587) is a potent inhibitor of Trk tyrosine kinases.
- Previous studies showed CEP-751 inhibits human neuroblastoma (NB) xenograft growth in mice.
Purpose of the Study:
- To investigate the mechanism of action of CEP-751 in neuroblastoma.
- To evaluate CEP-751's efficacy in TrkB-expressing neuroblastoma models.
Main Methods:
- Utilized SY5Y human NB cells and TrkB-transfected subclones (G8, G12) grown as xenografts.
- Administered CEP-751 (21 mg/kg) or vehicle control twice daily.
- Assessed TrkB expression via RT-PCR, BDNF-induced TrkB activation by immunoprecipitation/Western blot, and apoptosis using TUNEL assay.
Main Results:
- CEP-751 minimally affected SY5Y tumors but slowed growth in TrkB-expressing G8 and G12 tumors.
- Confirmed TrkB expression in G8/G12 but not SY5Y tumors.
- Demonstrated CEP-751 dose-dependently inhibited BDNF-induced TrkB activation and induced apoptosis in tumors.
Conclusions:
- CEP-751's therapeutic effect is partly due to TrkB kinase inhibition.
- CEP-751 shows potential as a treatment for aggressive neuroblastomas expressing TrkB.
