Drug repositioning in head and neck squamous cell carcinoma: An integrated pathway analysis based on connectivity map and differential gene expression

Abstract

The severe damage to health and social burden caused by head and neck squamous cell carcinoma (HNSCC) generated an urgent need to develop novel anti-cancer therapy. Currently, drug repositioning has risen in responses to the proper time as an efficient approach to invention of new anti-cancer therapies. In the present study, we aimed to screen candidate drugs for HNSCC by integrating HNSCC-related pathways from differentially expressed genes (DEGs) and drug-affected pathways from connectivity map (CMAP). We also endeavored to unveil the molecular mechanism of HNSCC through creating drug-target network and protein-to-protein (PPI) network of component DEGs in key overlapping pathways. As a result, a total of 401 DEGs were obtained from TCGA and GTEx mRNA-seq data. Taking the intersection part of 27 HNSCC-related Kyoto Encyclopedia of Genes and Genomes pathways and 33 drug-affected pathways, we retained 22 candidate drugs corresponding to two key pathways (cell cycle and p53 signaling pathways) of the five overlapping pathways. Two of the hub genes (PCNA and CCND1) identified from the PPI network of component DEGs in cell cycle and p53 signaling pathways were defined as the critical targets of candidate drugs with increased protein expression in HNSCC tissues, which was reported by the human protein atlas (HPA) database and cBioPortal. Finally, we validated via molecular docking analysis that two drugs with unknown effects in HNSCC: MG-262 and bepridil might perturb the development of HNSCC through targeting PCNA. These candidate drugs possessed broad application prospect as medication for HNSCC.

Keywords: Candidate drugs; Connectivity map; Drug repositioning; Head and neck squamous cell carcinoma; Molecular docking; Pathways.