Targeting Anaplastic Lymphoma Kinase (ALK) in Rhabdomyosarcoma (RMS) with the Second-Generation ALK Inhibitor Ceritinib.
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ICR Authors
Authors
van Erp, AEM
Hillebrandt-Roeffen, MHS
van Houdt, L
Fleuren, EDG
van der Graaf, WTA
Versleijen-Jonkers, YMH
Hillebrandt-Roeffen, MHS
van Houdt, L
Fleuren, EDG
van der Graaf, WTA
Versleijen-Jonkers, YMH
Document Type
Journal Article
Date
2017-12
Date Accepted
Date Available
Abstract
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.To determine the in vitro and in vivo effects and mechanism of action of the second-generation ALK inhibitor ceritinib on RMS cell growth.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.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.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.
Citation
Targeted oncology, 2017, 12 (6), pp. 815 - 826
Source Title
Publisher
ISSN
1776-2596
eISSN
1776-260X
Collections
Research Team
Clinical and Translational Sarcoma