Format

Send to

Choose Destination
Target Oncol. 2017 Dec;12(6):815-826. doi: 10.1007/s11523-017-0528-z.

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

Author information

1
Department of Medical Oncology, Radboud University Medical Center, P.O. Box 9101, 6500HB, Nijmegen, The Netherlands. anke.em.vanerp@radboudumc.nl.
2
Department of Medical Oncology, Radboud University Medical Center, P.O. Box 9101, 6500HB, Nijmegen, The Netherlands.
3
Clinical Studies, Clinical and Translational Sarcoma/Gene Function, The Institute of Cancer Research, London, SW3 6JB, UK.
4
The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, SW7 3RP, UK.

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.

PMID:
29067644
PMCID:
PMC5700232
DOI:
10.1007/s11523-017-0528-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center