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

Adamska, Aleksandra LU ; Chahin, Hanna LU orcid ; Muciño-Olmos, Erick Andrés LU orcid ; Esfandyari, Javanshir LU ; Aaltonen, Kristina LU orcid ; Granados-Aparici, Sofia ; Siaw, Joachim Tetteh LU orcid ; Radke, Katarzyna LU ; Lago, Chiara LU and Pasikowski, Paweł , et al. (2026) In Journal of Experimental and Clinical Cancer Research 45.
Abstract

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... (More)

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.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-026-03647-0.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Experimental and Clinical Cancer Research
volume
45
article number
58
publisher
BioMed Central (BMC)
external identifiers
  • pmid:41652432
ISSN
1756-9966
DOI
10.1186/s13046-026-03647-0
language
English
LU publication?
yes
id
c45ecc81-85e1-4556-afc2-0f6f856c6c93
date added to LUP
2026-02-25 15:39:18
date last changed
2026-02-27 03:49:54
@article{c45ecc81-85e1-4556-afc2-0f6f856c6c93,
  abstract     = {{<p>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.</p><p>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.</p><p>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.</p><p>CONCLUSIONS: Inhibition of the translational machinery by GSPT1-degrading molecular glues shows therapeutic potential in chemoresistant MYCN-amplified NB.</p><p>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-026-03647-0.</p>}},
  author       = {{Adamska, Aleksandra and Chahin, Hanna and Muciño-Olmos, Erick Andrés and Esfandyari, Javanshir and Aaltonen, Kristina and Granados-Aparici, Sofia and Siaw, Joachim Tetteh and Radke, Katarzyna and Lago, Chiara and Pasikowski, Paweł and Pluta, Roman and Sawicka, Anna and Glaza, Przemysław and Gisselsson, David and Navarro, Samuel and Noguera, Rosa and Majkut, Joanna and Dobrzański, Paweł and Cottens, Sylvain and Walczak, Michał J and Bexell, Daniel}},
  issn         = {{1756-9966}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Journal of Experimental and Clinical Cancer Research}},
  title        = {{GSPT1-specific protein degradation is effective in preclinical models of chemoresistant MYCN-amplified neuroblastoma}},
  url          = {{http://dx.doi.org/10.1186/s13046-026-03647-0}},
  doi          = {{10.1186/s13046-026-03647-0}},
  volume       = {{45}},
  year         = {{2026}},
}