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

Narendra Bharathy, Matthew N. Svalina, Teagan P. Settelmeyer, Megan M. Cleary, Noah E. Berlow, Susan D. Airhart, Sunny Xiang, James Keck, James B. Hayden, Jack F. Shern, Atiya Mansoor, Melvin Lathara, Ganapati Srinivasa, David M. Langenau, Charles Keller

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)62976-62983
Number of pages8
JournalOncotarget
Volume8
Issue number38
DOIs
StatePublished - 2017

Keywords

  • GSK3β
  • Myodifferentiation
  • Patient-derived xenograft
  • Preclinical testing
  • Rhabdomyosarcoma

ASJC Scopus subject areas

  • Oncology

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    Bharathy, N., Svalina, M. N., Settelmeyer, T. P., Cleary, M. M., Berlow, N. E., Airhart, S. D., Xiang, S., Keck, J., Hayden, J. B., Shern, J. F., Mansoor, A., Lathara, M., Srinivasa, G., Langenau, D. M., & Keller, C. (2017). Preclinical testing of the glycogen synthase kinase-3β inhibitor tideglusib for rhabdomyosarcoma. Oncotarget, 8(38), 62976-62983. https://doi.org/10.18632/oncotarget.18520