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.
Highlights
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma and is broadly classified into two histologic subtypes: alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma.aRMS is a highly aggressive tumor is characterized by the pathogenomic t(1:13) or t(2:13) translocation resulting in the chimeric gene-fusion product PAX3:FOXO1 or PAX7:FOXO1, respectively [1]. embryonal RMS (eRMS) is often defined as a RAS driven tumor [2,3,4]
These results suggest that as monotherapy, Glycogen synthase kinase 3β (GSK3β) inhibitors may not be a viable treatment for aRMS or eRMS
ARMS is a highly aggressive tumor is characterized by the pathogenomic t(1:13) or t(2:13) translocation resulting in the chimeric gene-fusion product PAX3:FOXO1 or PAX7:FOXO1, respectively [1]. eRMS is often defined as a RAS driven tumor [2,3,4]
Summary
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma and is broadly classified into two histologic subtypes: alveolar rhabdomyosarcoma (aRMS) and embryonal rhabdomyosarcoma (eRMS).aRMS is a highly aggressive tumor is characterized by the pathogenomic t(1:13) or t(2:13) translocation resulting in the chimeric gene-fusion product PAX3:FOXO1 or PAX7:FOXO1, respectively [1]. eRMS is often defined as a RAS driven tumor [2,3,4]. RMS has been shown experimentally to have a myogenic cell-of-origin in www.impactjournals.com/oncotarget some model systems and displays a poorly differentiated phenotype with gene expression profiles similar to fetal or regenerating muscle [5, 6]. Inhibition of GSK3β induces muscle differentiation [9, 10]; pharmacologic inhibition of GSK3β has been suggested to be a possible therapeutic avenue towards myodifferentiation in RMS [11]. To this end, recent studies have explored molecularlytargeted therapies that overcome the impaired differentiation in rhabdomyosarcoma [12,13,14,15]. We examined the in vivo effect of pharmacologic GSK3β inhibition in aRMS and eRMS
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
