Preclinical testing of the glycogen synthase kinase-3beta inhibitor tideglusib for rhabdomyosarcoma.

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Bharathy N, Svalina MN, Settelmeyer TP, Cleary MM, Berlow NE, Airhart SD, Xiang S, Keck J, Hayden JB, Shern JF, Mansoor A, Lathara M, Srinivasa G, Langenau DM, Keller C

Preclinical testing of the glycogen synthase kinase-3beta inhibitor tideglusib for rhabdomyosarcoma.

Oncotarget. 2017 Jun 16;8(38):62976-62983. doi: 10.18632/oncotarget.18520. eCollection 2017 Sep 8.

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28968964 [ View in PubMed
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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. GSK3beta 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 GSK3beta 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 GSK3beta-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, GSK3beta inhibitors may not be a viable treatment for aRMS or eRMS.

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