期刊
NEOPLASIA
卷 26, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2022.100776
关键词
Neuroblastoma; Pediatric oncology; Small molecule inhibitor; p53; Proteome; Phosphoproteome
类别
资金
- Center for Cancer Research, Intramural Research Program at the National Cancer Institute
- American Lebanese Syrian Associated Charities of St. Jude Childrens Research Hospital [CA191207]
- Department of Defense
This study suggests a potential therapeutic benefit in using selinexor and alisertib to synergistically increase p53-mediated cytotoxicity of high-risk neuroblastoma.
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.
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