The WNT Inhibitor PRI-724 Depletes Endogenous SOX2 and Blocks SOX2 Upregulation by Therapeutic Regimes

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Abstract
Background/Objectives: The stem cell transcription factor SOX2 is expressed in more than 20 types of cancer. SOX2 expression is also elevated by a wide range of clinically used drugs and has been linked causally to drug and radiation resistance. Hence, SOX2 is recognized as an important therapeutic target. This study set out to identify a small molecule inhibitor that reduces SOX2 in a wide range of tumor types. Methods: In this study, the WNT inhibitor, PRI-724 (Foscenvivint), was tested for its ability to downregulate SOX2 in ten tumor cell lines using western blot analysis. We also used western blot analysis to examine whether PRI-724 blocks the upregulation of SOX2 by clinically used drugs and radiation. Additionally, we examined the overall effects of PRI-724 on the transcriptome by performing RNA-Seq and STRING analysis. Results: PRI-724 not only downregulated SOX2 in ten different tumor cell lines representing eight different tumor types, but also blocked the upregulation of SOX2 induced by vemurafenib, gemcitabine and radiation. Besides downregulating SOX2 at the protein and RNA level, without altering the stability of SOX2 RNA, PRI-724 significantly modified the transcriptome. STRING analysis of the upregulated and downregulated genes indicates that PRI-724 altered the expression of genes involved in stress-response pathways, including endoplasmic reticulum (ER) stress. Conclusions: The WNT inhibitor PRI-724 downregulates SOX2 expression in a wide range of tumor cell types and blocks the upregulation of SOX2 by clinically used regimens. PRI-724 also modulates the expression of genes associated with stress-response pathways.
Funding Information
  • Nebraska Department of Health and Human Services (2026-30)
  • Nebraska Department of Health and Human Services (2027-34)
  • Pediatric Cancer Research Group
  • Edna Ittner Pediatric Research Support Fund

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