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[Cancer Research 62, 6462-6466, November 15, 2002]
© 2002 American Association for Cancer Research


Advances in Brief

Resistance to Chemotherapy Mediated by TrkB in Neuroblastomas1

Ruth Ho, Angelika Eggert, Tomoro Hishiki, Jane E. Minturn, Naohiko Ikegaki, Patricia Foster, Anna Marie Camoratto, Audrey E. Evans and Garrett M. Brodeur2

Division of Oncology, the Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania 19104 [R. H., A. E., T. H., J.E.M, N. I., P. F., A. E. E., G. M. B.], and Cephalon, Inc, West Chester, Pennsylvania 19380 [A. M. C.]

Neuroblastoma is a common childhood tumor derived from the peripheral nervous system. Favorable neuroblastomas usually express TrkA, the receptor for nerve growth factor (NGF), whereas unfavorable, MYCN-amplified neuroblastomas usually express TrkB and its ligand, brain-derived neurotrophic factor (BDNF). Here, we provide evidence that the TrkB-BDNF pathway is associated with enhanced survival and resistance to chemotherapy in neuroblastoma. We transfected the neuroblastoma line SH-SY5Y, which has endogenous expression of BDNF, with a full-length TrkB expression vector, and obtained clones with moderate or high levels of expression. Cells were exposed in vitro to chemotherapy agents used to treat neuroblastomas: doxorubicin, etoposide (VP16), and cisplatin. Chemoresistance was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cell survival and by ELISA for cell death. In all cases, the TrkB-expressing subclones were more resistant to treatment than the parent line. Furthermore, when the TrkB tyrosine kinase was blocked with the Trk-specific inhibitor CEP-2563, or by neutralizing antibody to BDNF, sensitivity to chemotherapy was significantly increased. We also found constitutive phosphorylation of AKT at the Ser-473 site in TrkB transfectants, whereas there was only a minimal level of constitutive phosphorylation of AKT in SY5Y cells. These results show that the TrkB-BDNF pathway provides a survival advantage when exposed to DNA-damaging reagents, and, therefore, this autocrine pathway may play an important role in mediating the drug-resistant phenotype associated with TrkB-expressing neuroblastomas. Activation of PI3K/AKT survival pathway may contribute to the increased drug resistance in TrkB-expressing neuroblastomas.




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Copyright © 2002 by the American Association for Cancer Research.