2. Academic Validation
  3. Combining selinexor with alisertib to target the p53 pathway in neuroblastoma

Combining selinexor with alisertib to target the p53 pathway in neuroblastoma

  • Neoplasia. 2022 Apr;26:100776. doi: 10.1016/j.neo.2022.100776.
Rosa Nguyen 1,  Hong Wang 2,  Ming Sun 3,  Dong Geun Lee 4,  Junmin Peng 5,  Carol J Thiele 6
Affiliations

Affiliations

  • 1 Pediatric Oncology Branch, NCI, Bethesda, MD, USA. Electronic address: hongharosa.nguyen@nih.gov.
  • 2 Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Pediatric Oncology Branch, NCI, Bethesda, MD, USA.
  • 4 Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 5 Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA; Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 6 Pediatric Oncology Branch, NCI, Bethesda, MD, USA. Electronic address: thielec@nih.gov.
PMID: 35217309 DOI: 10.1016/j.neo.2022.100776
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.

Keywords

Neuroblastoma; Pediatric oncology; Phosphoproteome; Proteome; Small molecule inhibitor; p53.

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