Identification of Therapeutic Targets and Novel Drug Candidates for Malignant Peripheral Nerve Sheath Tumors

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive form of sarcomas with a poor prognosis and limited treatment options. Therefore, new therapeutic targets are urgently needed to identify novel drugs.

Methods: Based on the Gene Expression Omnibus database, an integrated analysis was performed to identify differentially expressed genes (DEGs) in MPNSTs compared to neurofibromas (NFs). Then functional enrichment analyses, protein-protein interaction (PPI) network construction, and hub gene selection were conducted. We explored DEG-guided repurposable drugs to treat MPNST based on the Library of Integrated Network-Based Cellular Signatures (LINCS) database. Furthermore, the binding affinity between predicted drug candidates and the MPNST-associated hub gene was calculated using molecular docking.

Results: We identified 89 DEGs in common with all three MPNSTs datasets. In the PPI networks, twist family bHLH transcription factor 1 () with higher node degrees was further evaluated as a therapeutic target. Cytochalasin-d, cabozantinib, everolimus, refametinib, and BGT-226 were extracted from the LINCS database, which showed lower normalized connectivity scores (-1.88, -1.81, -1.78, -1.76, and -1.72, respectively) and was considered as drug candidates. In addition, the results of molecular docking between the five drugs and showed a binding affinity of -6.61, -7.03, -7.73, -3.94, and -7.07 kcal/mol, respectively.

Conclusions: Overall, our results describe the importance of in MPNST pathogenesis. Everolimus was also found to be a potential therapeutic drug for MPNSTs.