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Combining selinexor with alisertib to target the p53 pathway in neuroblastoma
Rosa Nguyen1, Hong Wang2, Ming Sun1
1Pediatric Oncology Branch, NCI, Bethesda, MD, USA.
Abstract:
Neuroblastoma accounts for 15% of cancer-related deaths in children, highlighting an unmet need for novel therapies. Selinexor is a small molecule inhibitor of XPO1. XPO1 shuffles cargo proteins with a nuclear export sequence from the nucleus to the cytosol, many of which are essential for cancer growth and cell maintenance. We systematically tested the effect of selinexor against neuroblastoma cells in vitro and in vivo and used an advanced proteomic and phosphoproteomic screening approach to interrogate unknown mechanisms of action. We found that selinexor induced its cytotoxic effects in neuroblastoma through the predominantly nuclear accumulation of p53 and global activation of apoptosis pathways. Selinexor also induced p53 phosphorylation at site S315, which is one initiating step for p53 degradation. Since this phosphorylation step is undertaken mostly by aurora kinase A (AURKA), we used the clinically available AURKA inhibitor, alisertib, and found p53-mediated lethality could be further augmented in three orthotopic xenograft mouse models. These findings suggest a potential therapeutic benefit using selinexor and alisertib to synergistically increase p53-mediated cytotoxicity of high-risk neuroblastoma.
Insights
Selinexor, an XPO1 inhibitor, shows promise against neuroblastoma by increasing p53 and apoptosis. Combining selinexor with alisertib, an AURKA inhibitor, further enhances this anti-cancer effect in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Neuroblastoma is a leading cause of pediatric cancer mortality, necessitating new therapeutic strategies.
- Exportin 1 (XPO1) is a key protein transporter involved in cancer cell survival.
- Selinexor is a novel small molecule inhibitor targeting XPO1.
Purpose of the Study:
- To investigate the efficacy and mechanism of action of selinexor in neuroblastoma.
- To explore the synergistic potential of selinexor with alisertib, an Aurora Kinase A (AURKA) inhibitor.
Main Methods:
- In vitro and in vivo testing of selinexor against neuroblastoma cells.
- Proteomic and phosphoproteomic screening to elucidate mechanisms.
- Evaluation of combination therapy with alisertib in orthotopic xenograft mouse models.
Main Results:
- Selinexor induced neuroblastoma cell death via nuclear accumulation of p53 and apoptosis.
- Selinexor treatment led to p53 phosphorylation at S315, a step in p53 degradation.
- Combination of selinexor and alisertib significantly enhanced p53-mediated lethality in preclinical models.
Conclusions:
- Selinexor demonstrates therapeutic potential for neuroblastoma by activating p53 and apoptosis.
- Dual inhibition of XPO1 and AURKA presents a promising synergistic strategy for high-risk neuroblastoma.
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