GSPT1-specific protein degradation is effective in preclinical models of chemoresistant MYCN-amplified neuroblastoma

BACKGROUND: High-risk neuroblastoma (HR-NB) is associated with therapy-resistant relapse, and novel therapeutic strategies are needed. GSPT1 is a GTPase involved in protein translation whose disruption may offer therapeutic potential in translation-dependent cancers. METHODS: GSPT1 expression was assessed in publicly available clinical data and tissue microarrays. GSPT1-degrading molecular glues were tested in MYCN-amplified NB organoids. Cell viability, cell death assays, western blotting, and proteomics were used to evaluate GSPT1 degraders. Effects on tumor growth and mouse survival were benchmarked against standard-of-care chemotherapy in a chemoresistant NB patient-derived xenograft (PDX) model. RNA sequencing and histopathological analysis were used to assess mechanisms of action in vivo. RESULTS: GSPT1 expression is associated with unfavorable outcomes in NB patients. Single-cell analysis revealed elevated GSPT1 expression in MYCN-amplified NB, whereas the E3 ligase CRBN (essential for protein degradation) was predominantly expressed in NB cells relative to non-malignant cells. GSPT1-specific degradation decreased cell viability and induced apoptosis in MYCN-amplified NB organoids and PDX models. GSPT1 degradation in vivo resulted in NB differentiation and suppression of MYCN and its related core regulatory gene networks. In vivo treatment further outperformed standard-of-care chemotherapy and increased survival in a highly chemoresistant NB PDX model. CONCLUSIONS: Inhibition of the translational machinery by GSPT1-degrading molecular glues shows therapeutic potential in chemoresistant MYCN-amplified NB.