Novel Signaling Pathway and NSC689534 as a Potential Drug Candidate for Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy of the skin, and its incidence is increasing annually. Once cSCC becomes metastatic, its associated mortality rate is much higher than that of cSCC in situ. However, the current treatments for progressive cSCC have several limitations. The aim of this study was to suggest a potential compound for future research that may benefit patients with cSCC.

In this study, we screened the following differentially expressed genes from the Gene Expression Omnibus database: GSE42677, GSE45164, GSE66359, and GSE98767. Using strategies such as protein-protein interaction network analysis and the CYTOSCAPE plugin MCODE, key modules were identified and then verified by Western blotting. Subsequently, related signalling pathways were constituted in the SIGNOR database. Finally, molecular docking analyses and cell viability assay were used to identify a potential candidate drug and verify its growth inhibition ability to A431 cell line.

Fifty-one common differentially expressed genes were screened and two key modules were identified. Among them, three core genes were extracted, constituting two signalling pathways, both of which belong to the module associated with mitotic spindles and cell division. A pathway involving CDK1, the TPX2-KIF11 complex, and spindle organization was validated in a series of analyses, including analyses for overall survival, genetic alteration, and molecular structure. Molecular docking analyses identified the pyridine 2-carbaldehyde thiosemicarbazone (NSC689534), which interacts with TPX2 and KIF11, as a potential candidate for the treatment of cSCC.

NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC.