RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition

Area of Science:

• Oncology
• Pediatric Cancer Research
• Molecular Biology

Background:

• High-risk neuroblastoma, a pediatric sympathetic nervous system tumor, is characterized by low mutation rates but frequent DNA copy number variations.
• Previous studies identified developmental drivers through segmental gains and amplifications.

Purpose of the Study:

• To identify novel therapeutic targets in high-risk neuroblastoma by analyzing gene dosage effects on expression and survival.
• To investigate the role of ribonucleotide reductase subunit M2 (RRM2) as a potential dependency factor.

Main Methods:

• Analysis of DNA copy number variants and gene expression in neuroblastoma.
• In vitro knockdown of RRM2 and assessment of growth inhibition.
• Development of a neuroblastoma zebrafish model coexpressing RRM2 and MYCN.
• Investigating the interplay between RRM2, MYCN, and the ATR-CHK1 signaling pathway.
• Evaluating combinatorial RRM2 and CHK1 inhibition in cell lines and patient-derived xenografts.

Main Results:

• Ribonucleotide reductase subunit M2 (RRM2) was identified as a candidate dependency factor.
• RRM2 knockdown inhibited tumor growth in vitro, and its co-overexpression with MYCN accelerated tumor formation in zebrafish.
• Forced RRM2 expression mitigated replicative stress from CHK1 inhibition.
• High RRM2 expression correlated with elevated CHK1 activity in human neuroblastomas.
• RRM2 inhibition amplified replication stress checkpoint dependency.
• Combined RRM2 and CHK1 inhibition demonstrated synergistic effects.

Conclusions:

• RRM2 is a critical dependency in high-risk neuroblastoma, particularly in the context of MYCN amplification.
• The ATR-CHK1 signaling pathway is intertwined with RRM2 function and replication stress response.
• Combined inhibition of RRM2 and CHK1 presents a promising synergistic therapeutic strategy for high-risk neuroblastoma.