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Published on: April 30, 2023
NPM1 as a potential therapeutic target for atypical teratoid/rhabdoid tumors
Ji Hoon Phi1,2, Choong-Hyun Sun3, Se-Hoon Lee4,5
1Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea.
Background:
Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets.
Methods:
Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines.
Results:
WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1. However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNA-Seq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells.
Conclusions:
We propose that NPM1 is a novel therapeutic target for AT/RTs.
Insights
Atypical teratoid/rhabdoid tumors (AT/RTs) show stable genomes but altered transcriptomes. Nucleophosmin (NPM1) is a promising therapeutic target, with inhibitors causing cell cycle arrest in AT/RT cells.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive pediatric brain cancers characterized by SMARCB1 gene inactivation.
- Understanding AT/RT genomic and transcriptomic alterations is crucial for identifying new therapeutic strategies.
Purpose of the Study:
- To analyze the genomic and transcriptomic profiles of human AT/RTs.
- To identify novel druggable targets for AT/RT treatment.
Main Methods:
- Whole exome sequencing (WES) and whole transcriptome sequencing (RNA-Seq) were performed on AT/RT tissues.
- Gene set enrichment and network analyses were utilized to identify key molecular players.
- Drug validation was conducted using AT/RT cell lines.
Main Results:
- AT/RT genomes are largely stable, with SMARCB1 inactivation being the primary genomic alteration.
- Significant transcriptomic dysregulation was observed, with 897 upregulated and 523 downregulated genes.
- Nucleophosmin (NPM1) was identified as the most upregulated gene, and its inhibition effectively reduced AT/RT cell viability and induced G1 cell cycle arrest.
Conclusions:
- Nucleophosmin (NPM1) represents a novel and promising therapeutic target for AT/RTs.
- Targeting NPM1 may offer a new avenue for treating these highly malignant brain tumors.
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