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Background <p>High-risk neuroblastoma (NB) is one of the most aggressive pediatric tumors accounting for 15% of all pediatric oncology deaths, and with less than 50% of patients experience long-term survival despite intense multimodal treatment. The tumor suppressor p53 is rarely (2%) mutated in NB but its functions are diminished in the majority of these tumors. Multiple mechanisms have been identified that attenuate the activity of p53 in MYCN-amplified (MYCN-amp) NB cells, but fewer mechanisms of p53 inactivation have been revealed in MYCN-WT NBs. Thus, a major challenge is to identify novel targeted therapies for high-risk NB (HR-NB) patients, specifically for the large fraction (70%) that present with MYCN-WT. Previously, we identified SETD8, the H4<sup>K20me1</sup> methyltransferase, as a crucial epigenetic regulator of growth and differentiation in NB. In addition to targeting other non-histone proteins, SETD8 monomethylates p53 on lysine 382 (p53<sup>K382me1</sup>), attenuating its pro-apoptotic and growth arrest functions. Genetic and pharmacological (UNC0379) inhibition of SETD8 impairs NB growth <i>in vivo</i>.</p> Methods <p>IC<sub>50</sub> and IVTI (<i>in vitro</i> therapeutic index) of SGSS05-NS3, a SETD8 inhibitor, were measured in a broad collection of MYCN-WT and MYCN-amp NB cell lines. We took advantage of RNA-seq transcriptome analysis, <i>in vitro</i> functional assays and <i>in vivo</i> preclinical NB models.</p> Results <p>To identify targeted therapies that are less toxic for HR-NB, we evaluated a more specific SETD8 inhibitor with enhanced activity and selectivity, SGSS05-NS3. Our results indicated that in NB cells <i>in vitro</i> treatment with SGSS05-NS3 rescues the canonical p53 functions leading to increases in p53 protein levels and of its target p21 by decreasing p53<sup>K382me1</sup>, impairing NB cell viability and inducing caspase-dependent cell death. Gene expression profile (RNA-seq analysis) confirmed that the most significantly upregulated genes upon SGSS05-NS3 treatment were among the p53 pathway targets. Pharmacological and genetic SETD8 inhibition restores p53-mediated DNA damage response. In pre-clinical xenograft NB models, pharmacological SETD8 inhibition by SGSS05-NS3 conferred a significant survival advantage in MYCN-WT NB.</p> Conclusions <p>Our study provides further evidence for targeting SETD8 as a therapeutic strategy in NB, alone or in combination with Topotecan.</p> Graphical Abstract <p></p>

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SGSS05-NS3, a covalent SETD8 inhibitor that activates p53 pathway in neuroblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月19日

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  • Zhihui Liu,
  • Sukriti Bagchi,
  • Chunhua Yan,
  • Ying Hu,
  • Gil Blum,
  • Anqi Ma,
  • Jian Jin,
  • Minkui Luo,
  • Sebastiano Di Bella,
  • Francesco Verona,
  • Ettore Appella,
  • Giuseppe Giannini,
  • Carol J. Thiele,
  • Veronica Veschi

摘要

Background

High-risk neuroblastoma (NB) is one of the most aggressive pediatric tumors accounting for 15% of all pediatric oncology deaths, and with less than 50% of patients experience long-term survival despite intense multimodal treatment. The tumor suppressor p53 is rarely (2%) mutated in NB but its functions are diminished in the majority of these tumors. Multiple mechanisms have been identified that attenuate the activity of p53 in MYCN-amplified (MYCN-amp) NB cells, but fewer mechanisms of p53 inactivation have been revealed in MYCN-WT NBs. Thus, a major challenge is to identify novel targeted therapies for high-risk NB (HR-NB) patients, specifically for the large fraction (70%) that present with MYCN-WT. Previously, we identified SETD8, the H4K20me1 methyltransferase, as a crucial epigenetic regulator of growth and differentiation in NB. In addition to targeting other non-histone proteins, SETD8 monomethylates p53 on lysine 382 (p53K382me1), attenuating its pro-apoptotic and growth arrest functions. Genetic and pharmacological (UNC0379) inhibition of SETD8 impairs NB growth in vivo.

Methods

IC50 and IVTI (in vitro therapeutic index) of SGSS05-NS3, a SETD8 inhibitor, were measured in a broad collection of MYCN-WT and MYCN-amp NB cell lines. We took advantage of RNA-seq transcriptome analysis, in vitro functional assays and in vivo preclinical NB models.

Results

To identify targeted therapies that are less toxic for HR-NB, we evaluated a more specific SETD8 inhibitor with enhanced activity and selectivity, SGSS05-NS3. Our results indicated that in NB cells in vitro treatment with SGSS05-NS3 rescues the canonical p53 functions leading to increases in p53 protein levels and of its target p21 by decreasing p53K382me1, impairing NB cell viability and inducing caspase-dependent cell death. Gene expression profile (RNA-seq analysis) confirmed that the most significantly upregulated genes upon SGSS05-NS3 treatment were among the p53 pathway targets. Pharmacological and genetic SETD8 inhibition restores p53-mediated DNA damage response. In pre-clinical xenograft NB models, pharmacological SETD8 inhibition by SGSS05-NS3 conferred a significant survival advantage in MYCN-WT NB.

Conclusions

Our study provides further evidence for targeting SETD8 as a therapeutic strategy in NB, alone or in combination with Topotecan.

Graphical Abstract