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A GCLC Inhibitor Enhances the Antitumor Efficacy of Glutathione Metabolic Pathway Inhibition in SMARCB1-Deficient Rhabdoid Tumors

ABSTRACT: Malignant rhabdoid tumors and epithelioid sarcomas, characterized by SMARCB1 deficiency, are aggressive cancers with limited effective treatments, necessitating development of therapeutic strategies. This study investigated the therapeutic efficacy and mechanism of action of inhibitors targeting glutamylcysteine ligase catalytic subunit (GCLC) in these intractable malignancies. The GCLC inhibitors GCLCi0 (ONO-6428513) and GCLCi1 (ONO-7068506) demonstrated high selectivity and potent anti-tumor effects in SMARCB1-deficient cancer cells in mouse tumor xenograft models, surpassing the efficacy of existing drugs. GCLC inhibition led to the depletion of intracellular glutathione (GSH), an increase in reactive oxygen species (ROS), and elevated lipid peroxidation, ultimately inducing ferroptotic cell death. SMARCB1-deficient cells exhibited reduced expression of SLC7A11, which led to low basal GSH levels and sensitivity to GCLC inhibition. Significant synergistic effects were observed when GCLC inhibitors were combined with agents targeting the GSH synthesis pathway, specifically SLC7A11 inhibitors and the glutaminase inhibitor telaglenastat. In a mouse tumor xenograft model, the combination of a GCLC inhibitor and telaglenastat showed superior anti-tumor efficacy compared to monotherapy, with good tolerability. These findings highlight the vulnerability of glutathione metabolism in SMARCB1-deficient cancers, suggesting that a GCLC inhibitor may be a promising therapeutic option. This study provides a preclinical foundation for the development of effective treatment strategies for SMARCB1-deficient cancers, including combination therapies, and supports further investigation toward future translational applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317224 | GEO | 2026/02/11

REPOSITORIES: GEO

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Project description:Glutathione (GSH) is a critical endogenous antioxidant that protects against intracellular oxidative stress. As such, pathological alterations in GSH levels are linked to a myriad of diseases including cancer, neurodegeneration and cataract. The rate limiting step in GSH biosynthesis is catalyzed by the glutamate cysteine ligase catalytic subunit (GCLC). The high expression of GCLC in the lens supports the synthesis of millimolar concentrations of GSH in this tissue. Herein, we describe the morphological consequences of deleting (knocking out) Gclc from surface ectoderm-derived ocular tissues (using the Le-Cre transgene; Gclc KO) which includes an overt microphthalmia phenotype and severely disrupted formation of multiple ocular structures (i.e., cornea, iris, lens, retina). Controlling for the Le-Cre transgene revealed that the deletion of Gclc significantly exacerbated the microphthalmia phenotype in Le-Cre hemizygous mice and resulted in dysregulated gene expression that was unique to only the lenses of KO mice. We further characterized the impaired lens development by conducting an RNA-seq experiment on KO and Gclc control (CON) mouse lens at the day of birth. RNA-sequencing revealed significant differences between Gclc knockout (KO) and Gclc control (CON) lenses, including down-regulation of crystallins and lens fiber cell identity genes, and up-regulation of lens epithelial cell identity genes. In addition, genes related to the immune system (e.g., immune system process, inflammatory response, neutrophil chemotaxis) were upregulated, and genes related to eye/lens development were downregulated. TRANSFAC analysis of differentially expressed genes (DEGs) in the lens of Gclc KO mice implicated PAX6 as a key upstream regulator of Gclc KO sensitive genes. This was further supported by a strong positive correlation between the transcriptomes of the lenses of Gclc KO and Pax6 KO mice. Strikingly, the dysregulation of PAX6-regulated genes in Gclc KO mice was observed despite no change in the ocular localization of PAX6 or decrease in the expression of PAX6 in the lens. In vitro experiments demonstrated that suppression of intracellular GSH concentrations resulted in impairment of PAX6 transactivation activity. Taken together, the present results elucidate a novel mechanism wherein intracellular GSH concentrations may modulate PAX6 activity.

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A GCLC Inhibitor Enhances the Antitumor Efficacy of Glutathione Metabolic Pathway Inhibition in SMARCB1-Deficient Rhabdoid Tumors

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