• Genomics-Guided Identification of ALK and TrkB as Therapeutic Targets in Neuroblastoma
  • Atousa Ghorbani,1,*
    1. Department of Biology, NT.C., Islamic Azad University, Tehran, Iran


  • Introduction: Neuroblastoma, one of the most common neuroectodermal tumors in childhood, is characterized by significant clinical heterogeneity and drug resistance. It accounts for approximately 7–10% of pediatric cancers, with an incidence of about 60–70 new cases per million children per year, predominantly affecting children under 5 years of age. High-risk patients often present with poor prognosis, early metastasis, and limited response to standard therapies, making treatment prediction challenging due to high genetic heterogeneity. Recent genomic analyses of The Cancer Genome Atlas (TCGA) have highlighted the role of TrkB pathway gene expression alterations in neuroblastoma progression. TrkB, a neurotrophin receptor, is associated with metastasis and drug resistance, representing a potential target for novel therapeutic strategies. This study aimed to investigate the role of the TrkB pathway in neuroblastoma using TCGA genomic data and to evaluate potential drug interactions with this target through in silico drug design.
  • Methods: This research is a genomic analysis and in silico drug design study. RNA-seq and mutation data from neuroblastoma patients were extracted from TCGA and analyzed to identify overexpressed genes and dominant signaling pathways (KEGG pathway analysis). For drug design, the crystal structure of TrkB (PDB 4AT4) was obtained from RCSB, and virtual screening was performed using AutoDock Vina on 20 known drugs and 50 DeepSite-selected compounds. Binding affinities and RMSD values were calculated for the best docking poses. Finally, two clinical drugs and two DeepSite-selected compounds were chosen for detailed molecular interaction analyses.
  • Results: TCGA data analysis revealed that increased TrkB (NTRK2) expression is associated with metastasis and reduced survival. Docking results showed that Entrectinib had the highest binding affinity to the TrkB active site (−9.6 kcal/mol, RMSD = 2.0 Å), while the two DeepSite-selected compounds demonstrated even higher binding affinities (−11.1 and −10.4 kcal/mol) with RMSD values of 1.6 Å and 1.9 Å, respectively. Molecular interaction analysis indicated stable hydrogen bond formation with the key residue Asp671.
  • Conclusion: Integrating TCGA genomic data with in silico drug design highlights TrkB as a promising therapeutic target in neuroblastoma. DeepSite-selected compounds show greater potential for developing innovative treatments, emphasizing the importance of personalized drug design based on patients’ genomic profiles.
  • Keywords: Neuroblastoma, ALK, TrkB, TCGA, In silico drug design