Preclinical testing of the glycogen synthase kinase-3β inhibitor tideglusib for rhabdomyosarcoma.
Document Type
Article
Publication Date
2017
JAX Source
Oncotarget 2017; 8(38):62976-62983
Volume
8
Issue
38
First Page
62976
Last Page
62983
ISSN
1949-2553
PMID
28968964
DOI
https://doi.org/10.18632/oncotarget.18520
Grant
CA168512
Abstract
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. RMS often arise from myogenic precursors and displays a poorly differentiated skeletal muscle phenotype most closely resembling regenerating muscle. GSK3β is a ubiquitously expressed serine-threonine kinase capable of repressing the terminal myogenic differentiation program in cardiac and skeletal muscle. Recent unbiased chemical screening efforts have prioritized GSK3β inhibitors as inducers of myodifferentiation in RMS, suggesting efficacy as single agents in suppressing growth and promoting self-renewal in zebrafish transgenic embryonal RMS (eRMS) models in vivo. In this study, we tested the irreversible GSK3β-inhibitor, tideglusib for in vivo efficacy in patient-derived xenograft models of both alveolar rhabdomyosarcoma (aRMS) and eRMS. Tideglusib had effective on-target pharmacodynamic efficacy, but as a single agent had no effect on tumor progression or myodifferentiation. These results suggest that as monotherapy, GSK3β inhibitors may not be a viable treatment for aRMS or eRMS. Oncotarget 2017; 8(38):62976-62983.
Recommended Citation
Bharathy N,
Svalina M,
Settelmeyer T,
Cleary M,
Berlow N,
Airhart S,
Xiang S,
Keck J,
Hayden J,
Shern J,
Mansoor A,
Lathara M,
Srinivasa G,
Langenau D,
Keller C.
Preclinical testing of the glycogen synthase kinase-3β inhibitor tideglusib for rhabdomyosarcoma. Oncotarget 2017; 8(38):62976-62983