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Targeted Oncology
Published in: Targeted Oncology 6/2017

Open Access 01-12-2017 | Original Research Article

Targeting Anaplastic Lymphoma Kinase (ALK) in Rhabdomyosarcoma (RMS) with the Second-Generation ALK Inhibitor Ceritinib

Authors: Anke E. M. van Erp, Melissa H. S. Hillebrandt-Roeffen, Laurens van Houdt, Emmy D. G. Fleuren, Winette T. A. van der Graaf, Yvonne M. H. Versleijen-Jonkers

Published in: Targeted Oncology | Issue 6/2017

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Abstract

Background

The receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) has been implicated in the tumorigenesis of rhabdomyosarcoma (RMS). However, the exact role of ALK in RMS is debatable and remains to be elucidated.

Objective

To determine the in vitro and in vivo effects and mechanism of action of the second-generation ALK inhibitor ceritinib on RMS cell growth.

Methods

Effects of ceritinib on cell proliferation, wound healing, cell cycle, and RTK signaling were determined in alveolar and embryonal rhabdomyosarcoma (ARMS, ERMS). In addition, possible synergistic effects of combined treatment with ceritinib and the Abl/Src family kinase inhibitor dasatinib were determined.

Results

Ceritinib treatment led to decreased cell proliferation, cell cycle arrest, apoptosis, and decreased in vivo tumor growth for the ARMS subtype. ERMS cell lines were less affected and showed no cell cycle arrest or apoptosis. Both subtypes lacked intrinsic ALK phosphorylation, and ceritinib was shown to affect the IGF1R signaling pathway. High levels of phosphorylated Src (Tyr416) were present following ceritinib treatment, making combined treatment with a Src inhibitor a potential treatment option. Combined treatment of ceritinib and dasatinib showed synergistic effects in both ERMS and ARMS cell lines.

Conclusion

This study shows that monotherapy with an ALK inhibitor, such as ceritinib, in RMS, has no effect on ALK signaling. However, the synergistic effects of ceritinib and dasatinib are promising, most probably due to targeting of IGF1R and Src.
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Metadata
Title
Targeting Anaplastic Lymphoma Kinase (ALK) in Rhabdomyosarcoma (RMS) with the Second-Generation ALK Inhibitor Ceritinib
Authors
Anke E. M. van Erp
Melissa H. S. Hillebrandt-Roeffen
Laurens van Houdt
Emmy D. G. Fleuren
Winette T. A. van der Graaf
Yvonne M. H. Versleijen-Jonkers
Publication date
01-12-2017
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 6/2017
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-017-0528-z

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