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A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma
Eveline Barbieri1, Katleen De Preter2, Mario Capasso3
1Texas Children's Cancer Center and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Abstract:
Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.
Insights
Small molecule MDM2 inhibitors, like Nutlin-3a, activate p53 signaling to induce apoptosis in neuroblastoma. Four specific genes (CHAF1A, RRM2, MCM3, MCM6) predict poor survival in neuroblastoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemotherapy relies on p53-mediated apoptosis for tumor regression.
- Neuroblastoma often exhibits repressed p53 signaling, contributing to its pathogenesis.
- MDM2-p53 inhibitors can restore p53 activity in cancers with intact downstream signaling.
Purpose of the Study:
- To investigate the p53 drug response signature in neuroblastoma using the MDM2 inhibitor Nutlin-3a.
- To identify genes regulated by p53 that are associated with neuroblastoma patient outcomes.
- To validate a gene expression signature predictive of survival in neuroblastoma.
Main Methods:
- Utilized Nutlin-3a, a small molecule MDM2 inhibitor, to treat neuroblastoma cells.
- Performed Gene Set Enrichment Analysis (GSEA) and pathway analysis to identify gene signatures.
- Employed multifactorial regression analysis and quantitative PCR for gene expression validation.
Main Results:
- Nutlin-3a treatment revealed p53-mediated apoptotic signatures.
- A set of p53-repressed genes were found to be over-expressed in high-risk neuroblastoma patients.
- A four-gene signature (CHAF1A, RRM2, MCM3, MCM6) strongly predicted overall and event-free survival.
Conclusions:
- MDM2-p53 inhibitors show potential for activating p53-dependent apoptosis in neuroblastoma.
- The identified four-gene signature serves as a robust prognostic biomarker for neuroblastoma.
- Transcriptional networks opposing p53 are crucial for aggressive neuroblastoma behavior and therapeutic resistance.
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