Transcriptomic Correlation Identifies Cell Model Representatives for <i>MYCN</i> -Amplified Pediatric Neuroblastoma, Downstream Impact of Model Choice on Functional Interpretation, and Potential Drug Repositioning Candidates

Neuroblastoma (NB) is the most common extracranial solid malignancy of children, and <i>MYCN</i> amplification defines a high-risk subtype with poor outcomes. Although widely used in preclinical drug discovery, NB cell lines are often selected based on availability rather than the molecular characteristics of patient-derived tumors, leading to a critical translational gap between experimental outcomes and clinical relevance. To address this, we developed a rank-based transcriptomic correlation framework to assess the concordance between patient-derived tumors (<i>n</i> = 642; combined from the SEQC/MAQC-III and TARGET cohorts) and publicly available NB cell lines (<i>n</i> = 39). This system-level analysis enabled the identification of cell model representatives (CMRs) that closely recapitulate the gene expression landscapes of clinical tumors. COG-N-557, SMS-KAN, and NB-SD emerged as the top CMRs for <i>MYCN</i>-amplified tumors, whereas COG-N-549, FELIX, and SK-N-SH were identified for <i>MYCN</i>-nonamplified tumors. Pathway enrichment analyses indicated that <i>MYCN</i>-amplified CMRs retain key transcriptional programs involved in neuronal development and tumor proliferation, supporting their biological relevance. Leveraging these models, we integrated pharmacogenomic connectivity mapping and drug-gene network analyses to uncover kinase inhibitors and epigenetic modulators as promising therapeutic candidates capable of targeting <i>MYCN</i>-driven transcriptional programs, despite <i>MYCN</i> being an undruggable oncogene. In conclusion, this study addresses a fundamental systems biology and translational research gap by establishing a data-driven framework for selecting NB cell lines that accurately reflect patient-derived tumor biology with direct implications for prioritizing therapeutically relevant drug candidates. Future studies should prioritize the top CMRs as <i>in vitro</i> models to enhance translational relevance and accelerate precision drug discovery in high-risk pediatric NB.